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1 Crystal structure of the dimeric phosphoenolpyruvate
carboxykinase (PEPCK) from Trypanosoma cruzi at 2 Å
resolution Original Research Article
Journal of Molecular Biology, Volume 313, Issue 5, 9 November 2001,
Pages 1059-1072
Stefano Trapani, Jutta Linss, Samuel Goldenberg, Hannes Fischer, Aldo
F. Craievich, Glaucius Oliva
Close preview | PDF (794 K) | Related articles | Related reference work articles
Abstract | Figures/Tables | References
Abstract
ATP-dependent phosphoenolpyruvate carboxykinase (PEPCK) (ATP: oxaloacetate carboxylyase
(transphosphorylating), EC 4.1.1.49) is a key enzyme involved in the catabolism of glucose and
amino acids in the parasite Trypanosoma cruzi, the causative agent of Chagas’ disease. Due to
the significant differences in the amino acid sequence and substrate specificity of the human
enzyme (PEPCK (GTP-dependent), EC 4.1.1.32), the parasite enzyme has been considered a
good target for the development of new anti-chagasic drugs. We have solved the crystal structure
of the recombinant PEPCK of T. cruzi up to 2.0 Å resolution, characterised the dimeric
organisation of the enzyme by solution small angle X-ray scattering (SAXS) and compared the
enzyme structure with the known crystal structure of the monomeric PEPCK from Escherichia
coli. The dimeric structure possesses 2-fold symmetry, with each monomer sharing a high degree
of structural similarity with the monomeric structure of the E. coli PEPCK. Each monomer folds
into two complex mixed α/β domains, with the active site located in a deep cleft between the
domains. The two active sites in the dimer are far apart from each other, in an arrangement that
seems to permit an independent access of the substrates to the two active sites. All residues of
the E. coli PEPCK structure that had been found to interact with substrates and metal cofactors
have been found conserved and in a substantially equivalent spatial disposition in the T. cruzi
PEPCK structure. No substrate or metal ion was present in the crystal structure. A sulphate ion
from the crystallisation medium has been found bound to the active site. Solution SAXS data
suggest that, in solutions with lower sulphate concentration than that used for the crystallisation
experiments, the actual enzyme conformation may be slightly different from its conformation in
the crystal structure. This could be due to a conformational transition upon sulphate binding,
similar to the ATP-induced transition observed in the E. coli PEPCK, or to crystal packing effects.
The present structure of the T. cruzi PEPCK will provide a good basis for the modelling of new
anti-chagasic drug leads.
Article Outline
• Introduction
• Results and discussion
• Quality of the refined crystallographic model
• The tertiary structure of the T. cruzi PEPCK
• The active site
• The quaternary structure
• Conclusions
• Materials and methods
• Protein expression, purification and crystallisation
• X-ray diffraction data collection and processing
• Structure solution and refinement
• SAXS data collection and processing
• Protein data bank accession numbers
• Acknowledgements
• References
2 Crystal structure of human cytosolic phosphoenolpyruvate

carboxykinase reveals a new GTP-binding site Original Research Article
Journal of Molecular Biology, Volume 316, Issue 2, 15 February 2002,
Pages 257-264
Pete Dunten, Charles Belunis, Robert Crowther, Kurt Hollfelder, Ursula
Kammlott, Wayne Levin, Hanspeter Michel, Gwendolyn B Ramsey, Amy
Swain, David Weber, Stanley J Wertheimer
Abstract
We report crystal structures of the human enzyme phosphoenolpyruvate carboxykinase (PEPCK)
with and without bound substrates. These structures are the first to be determined for a GTP-
dependent PEPCK, and provide the first view of a novel GTP-binding site unique to the GTP-
dependent PEPCK family. Three phenylalanine residues form the walls of the guanine-binding
pocket on the enzyme’s surface and, most surprisingly, one of the phenylalanine side-chains
contributes to the enzyme’s specificity for GTP. PEPCK catalyzes the rate-limiting step in the
metabolic pathway that produces glucose from lactate and other precursors derived from the citric
acid cycle. Because the gluconeogenic pathway contributes to the fasting hyperglycemia of type II
diabetes, inhibitors of PEPCK may be useful in the treatment of diabetes.
Article Outline
Introduction
Results
Complex with GTP
Comparison with ATP-dependent PEPCK
Complex with PEP
Substrate-free enyzme
Discussion
Materials and methods
Structure determination
Binding of nucleotides
Acknowledgements
References
3 Phosphoenolpyruvate carboxykinase: Structure, function and

regulation Review Article
Advances in Botanical Research, Volume 38, 2002, Pages 93-189
R. P. Walker, Z. -H. Chen
Abstract | References
Abstract
The aim of this article is to outline our understanding of the enzyme phosphoenolpyruvate
carboxykinase (PEPCK). Although emphasis is placed on the enzyme derived from flowering
plants, other organisms are also considered, because comparative studies provide invaluable
information. The following points are considered in detail. Firstly, the possibility that PEPCK in all
organisms arose from a common ancestor, and that the extension of about 12 kDa at the N-
terminus of PEPCK-ATP from flowering plants, which is not possessed by PEPCK-ATP from other
organisms, is homologous to the N-terminal region of PEPCK-GTP. Secondly, the regulation of
PEPCK activity in flowering plants by reversible protein phosphorylation is described.
Phosphorylation of the N-terminal extension possessed by PEPCK from flowering plants reduces
its catalytic velocity several-fold at physiological concentrations of oxaloacetate. How this is likely
to contribute to regulation of PEPCK in vivo is described. Thirdly, it is proposed that in flowering
plants PEPCK plays a widespread role as a component of a mechanism that counteracts
intracellular acidification. The proposed role of PEPCK in this mechanism is similar to that in the
kidney during acidosis.
Article Outline
• References
4 Crystal Structure of HPr Kinase/Phosphatase from Mycoplasma

pneumoniae Original Research Article
Journal of Molecular Biology, Volume 326, Issue 4, 28 February 2003,
Pages 1203-1217
Gregory S. Allen, Katrin Steinhauer, Wolfgang Hillen, Jörg Stülke, Richard
G. Brennan
Abstract
HPr kinase/phosphatase (HPrK/P) modifies serine 46 of histidine-containing protein (HPr), the
phosphorylation state of which is the control point of carbon catabolite repression in low G+C
Gram-positive bacteria. To understand the structural mechanism by which HPrK/P carries out its
dual, competing activities we determined the structure of full length HPrK/P from Mycoplasma
pneumoniae (PD8 ID, 1KNX) to 2.5 Å resolution. The enzyme forms a homo-hexamer with each
subunit containing two domains connected by a short loop. The C-terminal domain contains the
well-described P-loop (Walker A box) ATP binding motif and takes a fold similar to
phosphoenolpyruvate carboxykinase (PEPCK) from Escherichia coli as recently described in other
HPrK/P structures. As expected, the C-terminal domain is very similar to the C-terminal fragment
of Lactobacillus casei HPrK/P and the C-terminal domain of Staphylococcus xylosus HPrK/P; the
N-terminal domain is very similar to the N-terminal domain of S. xylosus HPrK/P. Unexpectedly,
the N-terminal domain resembles UDP-N-acetylmuramoyl-L-alanyl-D-glutamate:meso-
diaminopimelate ligase (MurE), yet the function of this domain is unclear. We discuss these
observations as well as the structural significance of mutations in the P-loop and HPrK/P family
sequence motif.
Article Outline
1. Introduction
2. Results
2.1. Monomer structure
2.2. Dimer Structure
2.3. Hexamer Structure
3. Discussion
3.1. P-loop
3.2. Structural homologues of the CTD
3.3. The kinase motifs
3.4. Kinase-1a
3.5. Kinase-2 motif
3.6. HPrK/P family sequence motif
3.7. Kinase-3
3.8. Structural homologues of the NTD
3.9. Mechanistic implications
3.10. Experimental Procedures
Acknowledgements
References
5 Kinetic characterization of recombinant human cytosolic

phosphoenolpyruvate carboxykinase with and without a His 10-
tag Original Research Article
Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1770,
Issue 11, November 2007, Pages 1576-1584
Christopher L. Case, Biswarup Mukhopadhyay
Abstract
We report the first kinetic characterization of human liver cytosolic GTP-dependent
phosphoenolpyruvate carboxykinase (GTP-PEPCK), which plays a major role in the development
of type 2 diabetes in human. In this work two recombinant forms of the enzyme were studied. One
form had a His10-tag and the other was His-tag-free, and with one exception, both exhibited similar
kinetic properties. When Mn2+ was used as the sole divalent cation, the His10-tagged enzyme, but
not the His-tag-free enzyme, was increasingly inhibited at Mn2+ concentrations greater than
0.7 mM. This inhibition did not pose any problem in kinetic analysis, for within the relevant Mn2+
concentration range the His-tagged human PEPCK behaved almost identically to the tag-free
enzyme. This property will bring simplicity and speed to purifying and studying multiple structural
variants of this important enzyme. Apparent Km values of tag-free enzyme for
phosphoenolpyruvate, GDP and bicarbonate were 450, 79 and 20,600 μM, respectively, while
those for oxaloacetate and GTP were 4 and 23 μM, respectively, emphasizing the enzyme's
gluconeogenic character. Bicarbonate (> 100 mM) inhibited OAA-forming activity, which was a
new observation with a GTP-PEPCK. The apparent Km for Mn2+ in the PEP-forming direction was
30-fold lower than that for the OAA-forming direction. Mn2+ and bicarbonate or CO2 might regulate
the enzyme in vivo.
Article Outline
1. Introduction
2. Materials and methods
2.1. Bacterial strains, growth media and culture conditions
2.2. Construction of an overexpression plasmid
2.3. Overexpression in E. coli and purification of recombinant human cytosolic PEPCK
2.4. Assays, SDS-PAGE and data analysis
3. Results
3.1. Expression and purification of recombinant human cytosolic phosphoenolpyruvate
carboxykinase
3.2. Effects of reducing agents and divalent cations on rHumcPEPCK and rHumcPEPCK-His10
activities
3.3. Substrate kinetics of recombinant human cytosolic phosphoenolpyruvate carboxykinase
4. Discussion
Acknowledgements
Appendix A. Supplementary data
References
6 Glycine N-methyltransferase affects the metabolism of aflatoxin B 1

and blocks its carcinogenic effect Original Research Article
Toxicology and Applied Pharmacology, Volume 235, Issue 3, 15 March
2009, Pages 296-304
Chia-Hung Yen, Jung-Hsien Hung, Yune-Fang Ueng, Shih-Ping Liu, Shih-
Yin Chen, Hsiao-Han Liu, Teh-Ying Chou, Ting-Fen Tsai, Ramalakshmi
Darbha, Ling-Ling Hsieh, Yi-Ming Arthur Chen
Abstract
Previously, we reported that glycine N-methyltransferase (GNMT) knockout mice develop chronic
hepatitis and hepatocellular carcinoma (HCC) spontaneously. For this study we used a
phosphoenolpyruvate carboxykinase promoter to establish a GNMT transgenic (TG) mouse model.
Animals were intraperitoneally inoculated with aflatoxin B1 (AFB1) and monitored for 11 months,
during which neither male nor female GNMT-TG mice developed HCC. In contrast, 4 of 6 (67%)
male wild-type mice developed HCC. Immunofluorescent antibody test showed that GNMT was
translocated into nuclei after AFB1 treatment. Competitive enzyme immunoassays indicated that
after AFB1 treatment, the AFB1–DNA adducts formed in stable clones expressing GNMT reduced
51.4% compared to the vector control clones. Experiments using recombinant adenoviruses
carrying GNMT cDNA (Ad-GNMT) further demonstrated that the GNMT-related inhibition of AFB1–
DNA adducts formation is dose-dependent. HPLC analysis of the metabolites of AFB1 in the
cultural supernatants of cells exposed to AFB1 showed that the AFM1 level in the GNMT group was
significantly higher than the control group, indicating the presence of GNMT can enhance the
detoxification pathway of AFB1. Cytotoxicity assay showed that the GNMT group had higher
survival rate than the control group after they were treated with AFB1. Automated docking
experiments showed that AFB1 binds to the S-adenosylmethionine binding domain of GNMT.
Affinity sensor assay demonstrated that the dissociation constant for GNMT–AFB1 interaction is
44.9 μM. Therefore, GNMT is a tumor suppressor for HCC and it exerts protective effects in
hepatocytes via direct interaction with AFB1, resulting in reduced AFB1–DNA adducts formation
and cell death.
Article Outline
Introduction
Plasmids construction
GNMT-TG mouse generation
Northern blot analysis
Western blot analysis
AFB1 challenge
Immunohistochemical staining
Cell culture and treatment
Immunofluorescent staining and confocal microscopy
Cytotoxicity assay
Competitive ELISA for quantifying AFB1–DNA adducts
AFB1 metabolism analysis
Determining GNMT–AFB1 complex dissociation constants
LGA dockings
Results
Establishment and characterization of a GNMT-TG mouse model
The carcinogenic effects of AFB1 are blocked by GNMT in the transgenic mice
AFB1 induces nuclear translocation of GNMT
GNMT antagonizes the cytotoxicity caused by AFB1
GNMT reduces AFB1–DNA adducts formation

GNMT affects AFB1 metabolism
Determination of the GNMT-AFB1 dissociation constant (Kd)
Modeling GNMT–AFB1 interaction
Discussion
Acknowledgements
References
7 Electron-transfer complexes in Ascaris mitochondria Review Article

Advances in Parasitology, Volume 51, 2002, Pages 95-131
Kiyoshi Kita, Shinzaburo Takamiya
Abstract
Parasites have developed a variety of physiological functions necessary for their survival within the
specialized environment of the host. Using metabolic systems that are very different from those of
the host, they can adapt to low oxygen tension present within the host animals. Most parasites do
not use the oxygen available within the host to generate ATP, but rather employ anaerobic
metabolic pathways. In addition, all parasites have a life cycle. In many cases, the parasite
employs aerobic metabolism during its free-living stage outside the host. In such systems, parasite
mitochondria play diverse roles. In particular, marked changes in the morphology and components
of the mitochondria during the life cycle are very interesting elements of biological processes such
as developmental control and environmental adaptation.
Recent research on the respiratory chain of the parasitic helminth Ascaris suum has shown that
the mitochondrial NADH-fumarate reductase system plays an important role in the anaerobic
energy metabolism of adult parasites inhabiting hosts, as well as describing unique features of the
developmental changes that occur during its life cycle.
Article Outline
• References
8 The Regulation of Carbon and Nutrient Assimilation in Diatoms is

Significantly Different from Green Algae Original Research Article
Protist, Volume 157, Issue 2, 13 June 2006, Pages 91-124
Christian Wilhelm, Claudia Büchel, Joachim Fisahn, Reimund Goss,
Torsten Jakob, Julie LaRoche, Johann Lavaud, Martin Lohr, Ulf Riebesell,
Katja Stehfest, Klaus Valentin, Peter G. Kroth
No abstract is available for this article.
Article Outline
Introduction
Biosynthesis of Photosynthetic Pigments
Light-Harvesting Organisation
Mechanism of Photoprotection
Properties of the Diadinoxanthin Cycle Enzymes of Diatoms
Regulation of Photosynthetic Electron Flow and the Fate of Photosynthetic Electrons
Regulation of the Enzyme Activity in the Calvin Cycle in Diatoms
Photorespiration
Carbon Acquisition in Diatoms
Synthesis and Breakdown of Storage Products under Starvation
Elemental Composition and Nutrient Uptake in Diatoms
Diatoms as Extremophiles
Conclusions
References
9 Peroxisome Proliferator-Activated Receptors

Comprehensive Toxicology, 2010, Chapter 2.09, Pages 145-167
J.P. Vanden Heuvel, J.M. Peters
Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor (NR)
superfamily that respond to changes in lipid and glucose homeostasis. Three PPAR subtypes (α,
β/δ and γ; NR1C1-3) have been identified in many species including humans. The manner in
which PPARs regulate gene expression includes association with retinoid-X-receptor (RXR) and
binding to specific response elements found on target genes. The subsequent alteration in gene
expression by the PPARs is influenced by kinases, cofactors, and other tissue specific factors.
Detailed examination of the structure–function of the PPARs allows for an understanding of certain
polymorphisms within the human population and may also aid in the design of new therapeutic
agents. The biological niches of PPARα, -β/δ and -γ are distinct, yet have many overlapping
functions. PPARα is the cognate receptor for peroxisome proliferators as well as certain fatty acid
and their metabolites. Through the extensive use of the PPARα-null mouse model, it is evident that
this receptor plays a key role in lipid homeostasis, particularly in the fasted state. Important fatty
acid oxidation enzymes, in peroxisomes and elsewhere, are regulated by PPARα. PPARγ has
received much attention as the target for antidiabetic drugs, but also plays a role in responding to
endogenous compounds such as prostaglandin J2. The ability of ectopically-expressed PPARγ to
induce differentiation of adipocytes, macrophages, and other cells, underscores the importance of
this protein in regulating cell fate and implies a role beyond fatty acid metabolism. PPARβ/δ
remains a somewhat under-appreciated member of this subfamily of receptors. The endogenous
ligands for PPARβ/δ are, as a group, relatively weak activators, but includes various fatty acids
and metabolites. The phenotype of the PPARβ/δ-null suggests an important role in lipid
homeostasis and this protein has received attention as a downstream target of growth regulatory
genes, in particular in the colon. Together, the PPARs represent an important target for
therapeutic and nutritional intervention due to their importance in maintaining cellular lipid
homeostasis.
Chapter Outline
2.09.1. Introduction
2.09.2. Structure–Function Relationship of PPARs
2.09.2.1. PPAR Phylogeny
2.09.2.2. PPAR Domains
2.09.2.3. Ligand-Dependent Activation
2.09.2.3.1. Exogenous activators
2.09.2.3.2. Endogenous activators
2.09.2.3.3. Selective PPAR modulators
2.09.2.4. Protein–Protein Interactions
2.09.2.4.1. Heterodimerization and DNA binding
2.09.2.4.2. Coregulator recruitment
2.09.2.4.3. Assembly, transport, and others
2.09.2.4.4. Phosphorylation of PPARs
2.09.2.4.4(i). PPARα
2.09.2.4.4(ii). PPARβ/δ
2.09.2.4.4(iii). PPARγ
2.09.3. Physiological Roles of PPARs
2.09.3.1. PPAR Target Genes
2.09.3.1.1. PPARα
2.09.3.1.2. PPARγ
2.09.3.1.3. PPARβ/δ
2.09.3.1.1(i). Regulation of PPAR expression
2.09.3.1.1(ii). PPAR function at the cellular level
2.09.3.1.1(iii). Whole animal physiology: Target gene disruption
2.09.4. Conclusion
Glossary
References
1 Structure/function studies of phosphoryl transfer by

0 phosphoenolpyruvate carboxykinase Review Article
Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics, Volume
1697, Issues 1-2, 11 March 2004, Pages 271-278
Louis T.J. Delbaere, Athena M. Sudom, Lata Prasad, Yvonne Leduc,
Hughes Goldie
Abstract
Phosphoenolpyruvate carboxykinase (PCK) catalyzes the conversion of oxaloacetate (OAA) to
PEP and carbon dioxide with the subsequent conversion of nucleoside triphosphate to
nucleoside diphosphate (NDP). The 1.9 Å resolution structure of Escherichia coli PCK consisted
of a 275-residue N-terminal domain and a 265-residue C-terminal domain with the active site
located in a cleft between these domains. Each domain has an α/β topology and the overall
structure represents a new protein fold. Furthermore, PCK has a unique mononucleotide-binding
fold. The 1.8 Å resolution structure of the complex of ATP/Mg2+/oxalate with PCK revealed a 20°
hinge-like rotation of the N- and C-terminal domains, which closed the active site cleft. The ATP
was found in the unusual syn conformation as a result of binding to the enzyme. Along with the
side chain of Lys254, Mg2+ neutralizes charges on the Pβ and Pγ oxygen atoms of ATP and
stabilizes an extended, eclipsed conformation of the Pβ and Pγ phosphoryl groups. The sterically
strained high-energy conformation likely lowers the free energy of activation for phosphoryl
transfer. Additionally, the γ-phosphoryl group becomes oriented in-line with the appropriate
enolate oxygen atom, which strongly supports a direct SN2-type displacement of this γ-
phosphoryl group by the enolate anion. In the 2.0 Å resolution structure of the complex of
PCK/ADP/Mg2+/AlF3, the AlF3 moiety represents the phosphoryl group being transferred during
catalysis. There are three positively charged groups that interact with the fluorine atoms, which
are complementary to the three negative charges that would occur for an associative transition
state.
Article Outline
1. Introduction
1.1. Phosphoenolpyruvate carboxykinase
1.2. Associative and dissociative phosphoryl transfer
2. Crystallographic procedures
3. Structural features
3.1. Tertiary structure
3.2. Substrate/inhibitor binding
3.3. Structures of the complexes of E. coli PCK with Mg2+/ATP/Mn2+/pyruvate and E. coli PCK
with Mg2+/ATP/Ca2+/pyruvate
4. Discussion
5. Mechanism of catalysis
6. Conclusions and perspectives
Acknowledgements
References
1 The phosphoryl-transfer mechanism of Escherichia coli phosphoenolpyruvate carboxykinase from the use of
1 Original Research Article
AlF3
Journal of Molecular Biology, Volume 314, Issue 1, 16 November 2001,
Pages 83-92
Athena M Sudom, Lata Prasad, Hughes Goldie, Louis T.J Delbaere
Abstract
The mechanism of reversible transfer of the γ-phosphate group of ATP by Escherichia coli
phosphoenolpyruvate carboxykinase (PCK) on to its substrate is of great interest. It is known that
metallofluorides are accurate analogs of the transition state in the context of kinase mechanisms.
Therefore, two complexes of PCK, one with AlF3, Mg2+ and ADP (complex I), the other with AlF3,
Mg2+, ADP and pyruvate (complex II) were crystallized. The X-ray crystal structures of these two
complexes were determined at 2.0 Å resolution. The Al atom has trigonal bipyramidal geometry
that mimics the transition state of phosphoryl transfer. The Al atom is at a distance of 2.8 Å and
2.9 Å from an oxygen atom of the β-phosphoryl group of ADP in complex I and II, respectively. A
water molecule in complex I and an oxygen atom of the pyruvate in complex II are located along
the axis of the trigonal bipyramid on the side opposite to the β-phosphoryl oxygen with respect to
the equatorial plane, suggesting that the complexes are close mimics of the transition state.
Along with the presence of positively charged species around the AlF3 moiety, these results
indicate that phosphoryl transfer occurs via a direct displacement mechanism with associative
qualities.
Article Outline
Introduction
Results
Discussion
Function of Mg2+ in PCK complexes
Enzyme activation by aluminum fluoride
Efficient enzymes and AlF3
PCK and AlF3
PCK transition state

Crystallization and data collection
Structure solution and refinement
Atomic coordinates
Acknowledgements
References
1 Benzoxazole benzenesulfonamides are novel allosteric inhibitors of

2 fructose-1,6-bisphosphatase with a distinct binding mode
Bioorganic & Medicinal Chemistry Letters, Volume 16, Issue 7, 1 April
2006, Pages 1811-1815
Thomas W. von Geldern, Chunqiu Lai, Rebecca J. Gum, Melissa Daly,
Chaohong Sun, Elizabeth H. Fry, Celerino Abad-Zapatero
Abstract
We have identified benzoxazole benzenesulfonamide 1 as a novel allosteric inhibitor of fructose-
1,6-bisphosphatase (FBPase-1). X-ray crystallographic and biological studies of 1 indicate a
distinct binding mode that recapitulates features of several previously reported FBPase-1
inhibitor classes.
Article Outline
Acknowledgements
References
Graphical abstract
1 Mechanisms of basal and kinase-inducible transcription activation

3 by CREB Review Article
Progress in Nucleic Acid Research and Molecular Biology, Volume 72,
2002, Pages 269-305
Patrick G. Quinn
Abstract
The CAMP response element (CRE)-binding protein (CREB) stimulates basal transcription of
CRE-containing genes and mediates induction of transcription upon phosphorylation by protein
kinases. The basal activity of CREB maps to a carboxy-terminal constitutive activation domain
(CAD), whereas phosphorylation and inducibility map to a central, kinase-Inducible domain (KID).
The CAD interacts with and recruits the promoter recognition factor TFIID through an interaction
with a specific TATA-binding-protein-associated factor (TAF), dTAFII101/hTAFII135. Interaction
between the TAF and the CAD is mediated by a central cluster of hydrophobic amino acids,
mutation of which disrupts TAF binding, polymerase recruitment, and transcription activation.
Assessment of the contributions of the CAD and KID to recruitment of the polymerase complex
versus enhancement of subsequent reaction steps (isomerization, promoter clearance, and
reinitiation) showed that the CAD and P-KID act in a concerted mechanism to stimulate
transcription. The CAD, but not the KID, mediated recruitment of a complex containing
components of a transcription initiation complex, including pol II, IIB, and IID. However, the CAD
was relatively ineffective in stimulating subsequent steps in the reaction mechanism. In contrast,
phosphorylation of the KID in CREB effectively stimulated isomerization of the recruited
polymerase complex and multiple-round transcription. A model for the activation of transcription
by phosphorylated CREB is proposed, in which the polymerase is recruited by interaction of the
CAD with TFIID and the recruited polymerase is activated further by phosphorylation of the kID in
CREB.
Article Outline
• References
1 Enzyme dynamics point to stepwise conformational selection in

4 catalysis Review Article
Current Opinion in Chemical Biology, Volume 14, Issue 5, October 2010,
Pages 652-659
Buyong Ma, Ruth Nussinov
Recent data increasingly reveal that conformational dynamics are indispensable to enzyme
function throughout the catalytic cycle, in substrate recruiting, chemical transformation, and
product release. Conformational transitions may involve conformational selection and induced fit,
which can be viewed as a special case in the catalytic network. NMR, X-ray crystallography,
single-molecule FRET, and simulations clearly demonstrate that the free enzyme dynamics
already encompass all the conformations necessary for substrate binding, preorganization,
transition-state stabilization, and product release. Conformational selection and substate
population shift at each step of the catalytic turnover can accommodate enzyme specificity and
efficiency. Within such a framework, entropy can have a larger role in conformational dynamics
than in direct energy transfer in dynamically promoted catalysis.
Article Outline
Introduction
Conformational selection and population shift constitute the catalytic network
Enzyme specificity can be controlled through multiple, consecutive conformational selection
steps
Conformational substates may help transition-state barrier crossing
Conclusions
References and recommended reading
Acknowledgements
References
1 INT131: A Selective Modulator of PPARγ Original Research Article

5 Journal of Molecular Biology, Volume 386, Issue 5, 13 March 2009,
Pages 1301-1311
Alykhan Motani, Zhulun Wang, Jennifer Weiszmann, Lawrence R.
McGee, Gary Lee, Qingxiang Liu, Jocelyn Staunton, Zexu Fang, Helen
Fuentes, Michelle Lindstrom, Jinsong Liu, Donna H.T. Biermann, Juan
Jaen, Nigel P.C. Walker, R. Marc Learned, Jin-Long Chen, Yang Li
Summary
The nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ; NR1C3)
plays a central role in adipogenesis and is the molecular target of the thiazolidinedione class of
antidiabetic drugs. To overcome the well-known shortcomings of thiazolidinediones, we have
identified INT131 (formerly T131 and AMG131) as a potent selective ligand for PPARγ that is
structurally and pharmacologically distinct from glitazone agonists. In vitro biochemical and cell-
based functional assays showed that INT131 mediates a distinct pattern of coregulator
recruitment to PPARγ. In adipocytes, INT131 showed minimal stimulation of adipocyte
differentiation and partially activated PPARγ target genes involved in adipogenesis and, at the
same time, showed more agonistic activity on another set of target genes that may influence
insulin sensitivity directly. These unique properties of INT131 may provide a mechanistic basis
for its distinct pharmacological profile. In vivo, increases in glucose tolerance were observed in
Zucker (fa/fa) rats following a 14-day oral treatment with INT131. Although the maximal efficacies
of INT131 and rosiglitazone were similar with respect to improvements in glucose tolerance,
INT131 had less effect on heart and lung weights, weight gain, hemodilution, and plasma
volume. Thus, INT131 appears to selectively modulate PPARγ responses in an in vivo preclinical
model, showing antidiabetic efficacy while exhibiting an improved hemodynamic and
cardiovascular adverse effect profile compared to the full agonist rosiglitazone. X-ray
crystallography revealed that INT131 interacts with PPARγ through a distinct binding mode,
forming primarily hydrophobic contacts with the ligand-binding pocket without direct hydrogen-
bonding interactions to key residues in helix 12 that are characteristic of full agonists.
Mutagenesis studies on Tyr473 in helix 12 demonstrated this residue as essential for
rosiglitazone-induced receptor activation, but nonessential for INT131 function in vitro, providing
one possible molecular determinant for INT131's distinct pharmacology. INT131 is currently
being evaluated in a clinical setting as a therapeutic agent for the treatment of type 2 diabetes.
Article Outline
Introduction
Results
INT131 is a potent and highly selective PPARγ partial agonist
INT131 does not have a direct contact with helix 12
INT131 is a context-dependent PPARγ modulator
INT131 weakly promoted in vitro differentiation of mouse preadipocytes and differentially induced
PPARγ target genes
In vivo profile of INT131 versus rosiglitazone
Discussion
Materials and Methods
In vitro reagents and assay protocol
Adipocyte differentiation and gene expression analysis
Site-directed mutagenesis
Cell culture and transient transactivation assay
In vivo profiling in the Zucker (fa/fa) rat model
Clinical chemistry
Protein preparation and crystallization
Data collection, structure determination, and refinement
Accession numbers
Acknowledgements
References
1 Genomic and genetic research on bursate nematodes: significance,

6 implications and prospects Original Research Article
International Journal for Parasitology, Volume 30, Issue 4, April 2000,
Pages 509-534
Robin B. Gasser, Susan E. Newton
Abstract
Molecular genetic research on parasitic nematodes (order Strongylida) is of major significance
for many fundamental and applied areas of medical and veterinary parasitology. The advent of
gene technology has led to some progress for this group of nematodes, particularly in studying
parasite systematics, drug resistance and population genetics, and in the development of
diagnostic assays and the characterisation of potential vaccine and drug targets. This paper
gives an account of the molecular biology and genetics of strongylid nematodes, mainly of
veterinary socio-economic importance, indicates the implications of such research and gives a
perspective on genome research for this important parasite group, in light of recent technological
advances and knowledge of the genomes of other metazoan organisms.
Article Outline
1. Introduction
2. Genome research: parasite identification, systematics, molecular evolution and population
genetics
2.1. Ribosomal DNA
2.1.1. Parasite identification and diagnostic implications
2.1.2. Systematics
2.1.3. Pre-rRNA structure predictions
2.1.4. Study of concerted evolution
2.2. Research into genetic variation and its implications
2.2.1. Mitochondrial DNA (mtDNA)
2.2.2. Polymorphic genetic markers
2.3. Conclusion
3. New approaches for investigating gene expression and function
3.1. Library construction and expressed sequence tags (ESTs)
3.2. Differentially expressed genes
3.3. Caenorhabditis elegans—a model system to test the expression and function of homologues
of parasite genes
4. Expressed genes: understanding parasite biology, and applications to control and diagnosis
4.1. Genes of fundamental, biological significance
4.2. Genes with potential for immunological control
4.2.1. Excretory/secretory molecules
4.2.2. Surface antigens
4.2.3. Somatic molecules
4.3. Expressed genes for use in the diagnosis of infections
4.4. Genes associated with drug resistance
4.5. Genes with potential for chemotherapeutic control
4.5.1. Enzymes of biochemical and metabolic pathways
4.5.2. Receptors and neuropeptides
4.5.3. Target validation and future directions
5. Future directions
Acknowledgements
References
1 New hepatic targets for glycaemic control in diabetes Review Article

7 Best Practice & Research Clinical Endocrinology & Metabolism, Volume
21, Issue 4, December 2007, Pages 587-605
Loranne Agius
Type-2 diabetes is associated with impaired glucose clearance by the liver in the postprandial
state, and with elevated glucose production in the post-absorptive state. New targets within the
liver are currently being investigated for development of antihyperglycaemic drugs for type-2
diabetes. They include glucokinase, which catalyses the first step in glucose metabolism, the
glucagon receptor, and enzymes of gluconeogenesis and/or glycogenolysis such as glucose 6-
phosphatase, fructose 1,6-bisphosphatase and glycogen phosphorylase. Preclinical studies with
candidate drugs on animal models or cell-based assays suggest that these targets have the
potential for pharmacological glycaemic control. Data from clinical studies is awaited. Further
work is required for better understanding of the implications of targeting these sites in terms of
possible side-effects or tachyphylaxis. The advantage of combined targeting of two or more sites
within the liver for minimizing side-effects and tachyphylaxis caused by single-site targeting is
discussed.
Article Outline
Hepatic glucose metabolism in the normal and diabetic state
Counteraction of glucagon binding or signalling
Inhibitors of glucose 6-phosphatase (G6Pase)
Inhibition of gluconeogenesis by fructose 1,6-bisphosphatase (F16BPase) inhibitors
Inhibition of glycogenolysis with glycogen phosphorylase inhibitors (GPIs)
Active-site inhibitors
AMP-site inhibitors
Indole-carboxamide-site inhibitors
Purine-nucleoside-site inhibitors
Efficacy of GPIs in man
Glucokinase activators (GKAs)
Combination targeting within the liver
Summary and perspectives
Acknowledgements
References
1 The signal recognition particle receptor mediates the GTP-

8 dependent displacement of SRP from the signal sequence of the
nascent polypeptide Original Research Article
Cell, Volume 57, Issue 4, 19 May 1989, Pages 599-610
Timothy Connolly, Reid Gilmore
Abstract
The signal recognition particle (SRP)-mediated transport of proteins across mammalian
endoplasmic reticulum requires GTP in a capacity distinct from polypeptide elongation. We
defined the role of GTP by a molecular characterization of translocation intermediates that
accumulate after incubation of SRP-ribosome complexes with microsomal membranes. SRP
receptor-catalyzed displacement of SRP from ribosomes was GTP-dependent both with intact
membranes and with the purified SRP receptor. GTP-specific binding was localized to the α
subunit of the receptor by photoaffinity labeling and by probing nitrocellulose blots of the receptor
with GTP. Analysis of the α subunit of the SRP receptor revealed amino acid sequences that are
similar to guanine ribonucleotide binding site consensus sequence elements.
1 Major Urinary Protein Regulation of Chemical Communication and

9 Nutrient Metabolism
Vitamins & Hormones, Volume 83, 2010, Chapter Chapter Six, Pages
151-163
Yingjiang Zhou, Liangyou Rui
Abstract
The major urinary protein (MUP) family members contain a conserved β-barrel structure with a
characteristic central hydrophobic pocket. They are secreted by the liver and excreted into the
urine. MUPs bind via their central pockets to volatile pheromones or other lipophilic molecules,
and regulate pheromone transportation in the circulation, excretion in the kidney, and release into
the air from urine marks. MUPs are highly polymorphic, and the MUP profiles in urine function as
individual identity signatures of the owners. The MUP signatures are detected by the main and
accessory olfactory systems and trigger adaptive behavioral responses and/or developmental
processes. Circulating MUPs serve as a metabolic signal to regulate glucose and lipid
metabolism. Recombinant MUP1 markedly ameliorates hyperglycemia and glucose intolerance
in mice with type 2 diabetes. MUP1 suppresses hepatic gluconeogenesis and promotes energy
expenditure in skeletal muscle by stimulating mitochondrial biogenesis and function. MUPs are
unique members of the lipocalin superfamily that mediate both chemical and metabolic signaling.
Article Outline
I. Introduction
II. MUP Structure and Polymorphism
A. MUPs bind to pheromones via their central β-barrel cavities
B. MUPs are highly polymorphic
III. MUP Regulation of Chemical Communication
A. MUPs function as volatile pheromone carriers
B. MUPs act as pheromones to directly regulate behavioral and physiological responses
C. The MUP profiles serve as an individual identity signature
IV. MUP Regulation of Nutrient Metabolism
A. MUP1 is involved in nutrient sensing
B. MUP1 regulates nutrient metabolism in multiple tissues
C. MUP1 regulates metabolism by multiple mechanisms
V. Conclusions and Future Directions
Acknowledgements
References
2 Structure of a GTP-dependent Bacterial PEP-carboxykinase from

0 Corynebacterium glutamicum Original Research Article
The International Journal of Biochemistry & Cell Biology, Volume 40,
Issue 8, 2008, Pages 1597-1603
Sanjukta Aich, Lata Prasad, Louis T.J. Delbaere
Abstract
GTP-dependent phosphoenolpyruvate carboxykinase (PCK) is the key enzyme that controls the
blood glucose level during fasting in higher animals. Here we report the first substrate-free
structure of a GTP-dependent phosphoenolpyruvate (PEP) carboxykinase from a bacterium,
Corynebacterium glutamicum (CgPCK). The protein crystallizes in space group P21 with four
molecules per asymmetric unit. The 2.3 Å resolution structure was solved by molecular
replacement using the human cytosolic PCK (hcPCK) structure (PDB ID: 1KHF) as the starting
model. The four molecules in the asymmetric unit pack as two dimers, and is an artifact of crystal
packing. However, the P-loop and the guanine binding loop of the substrate-free CgPCK
structure have different conformations from the other published GTP-specific PCK structures,
which all have bound substrates and/or metal ions. It appears that a change in the P-loop and
guanine binding loop conformation is necessary for substrate binding in GTP-specific PCKs, as
opposed to overall domain movement in ATP-specific PCKs.
Article Outline
1. Introduction
2.1. Materials
2.2. Purification and crystallization
2.3. Data collection and analysis
2.4. Structure determination and refinement
2.5. Fluorescence studies
3. Results
3.1. Structure of CgPCK
3.2. Fluorescence studies
4. Discussion
Acknowledgements
References
2 Comparison of mouse hepatic mitochondrial versus microsomal

1 cytochromes P450 following TCDD treatment Original Research Article
Biochemical and Biophysical Research Communications, Volume 342,
Issue 4, 21 April 2006, Pages 1375-1381
Mary Beth Genter, Corey D. Clay, Timothy P. Dalton, Hongbin Dong,
Daniel W. Nebert, Howard G. Shertzer
Abstract
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) induces cytochromes P450 (CYPs) such as CYP1A1
and CYP1A2 via activation of the aromatic hydrocarbon receptor (AHR). Herein we describe the
TCDD-dependent enrichment of CYPs in liver microsomes and mitoplasts from C57BL/6J mice.
TCDD-induced accumulation of CYP1A1 and CYP1A2 was observed in microsomes and
mitoplasts after treatment with 15 μg TCDD/kg/d for 3 d. While microsomal CYP1 proteins
peaked at 1 week and diminished thereafter, mitoplast CYP1 proteins persisted 8 weeks at high
levels. TCDD also induced microsomal CYP2A5, but not microsomal proteins immunoreactive to
CYP2C11, CYP3A2 or CYP4A1 antibodies. Nevertheless, each of these proteins increased in
mitoplasts following TCDD exposure. These results suggest that TCDD increases mitochondrial
CYP immunoreactive proteins under the transcriptional control of the AHR, as well as CYPs that
are not under AHR control. We speculate that such mitochondrial CYPs may be involved in the
generation, or mitigation, of the well-known TCDD-inducible oxidative stress response.
Article Outline
Results
CYP1A1 and CYP1A2
CYP2A5, POR, and EPHX1
CYP2C, CYP3A2, and CYP4A
Discussion
Acknowledgements
References
2 Crystal structure of Anaerobiospirillum succiniciproducens PEP

2 carboxykinase reveals an important active site loop Original
Research Article
The International Journal of Biochemistry & Cell Biology, Volume 37,
Issue 9, September 2005, Pages 1829-1837
Julien J.H. Cotelesage, Lata Prasad, J. Gregory Zeikus, Maris
Laivenieks, Louis T.J. Delbaere
Abstract
The 2.2 Å resolution crystal structure of the enzyme phosphoenolpyruvate carboxykinase (PCK)
from the bacterium Anaerobiospirillum succiniciproducens complexed with ATP, Mg2+, Mn2+ and
the transition state analogue oxalate has been solved. The 2.4 Å resolution native structure of A.
succiniciproducens PCK has also been determined. It has been found that upon binding of
substrate, PCK undergoes a conformational change. Two domains of the molecule fold towards
each other, with the substrates and metal ions held in a cleft formed between the two domains.
This domain movement is believed to accelerate the reaction PCK catalyzes by forcing bulk
solvent molecules out of the active site. Although the crystal structure of A. succiniciproducens
PCK with bound substrate and metal ions is related to the structures of PCK from Escherichia
coli and Trypanosoma cruzi, it is the first crystal structure from this class of enzymes that clearly
shows an important surface loop (residues 383–397) from the C-terminal domain, hydrogen
bonding with the peptide backbone of the active site residue Arg60. The interaction between the
surface loop and the active site backbone, which is a parallel β-sheet, seems to be a feature
unique of A. succiniciproducens PCK. The association between the loop and the active site is the
third type of interaction found in PCK that is thought to play a part in the domain closure. This
loop also appears to help accelerate catalysis by functioning as a ‘lid’ that shields water
molecules from the active site.
Article Outline
1. Introduction
2. Methods
2.1. Protein purification
2.2. Crystallization conditions
2.3. Data processing and structure solution
2.4. Protein data bank accession numbers
3. Results
3.1. Overall structure
3.2. Substrate binding
3.3. Metal binding
3.4. Domain movement
3.5. Visualization of disordered loop
4. Discussion
Acknowledgements
References
2 E2F Repression by C/EBPα Is Required for Adipogenesis and

3 Granulopoiesis In Vivo Original Research Article
Cell, Volume 107, Issue 2, 19 October 2001, Pages 247-258
Bo T. Porse, Thomas Å. Pedersen, Xiufeng Xu, Bo Lindberg, Ulla M.
Wewer, Lennart Friis-Hansen, Claus Nerlov
Abstract
The C/EBPα transcription factor is required for differentiation of adipocytes and neutrophil
granulocytes, and controls cellular proliferation in vivo. To address the molecular mechanisms of
C/EBPα action, we have identified C/EBPα mutants defective in repression of E2F-dependent
transcription and found them to be impaired in their ability to suppress cellular proliferation, and
to induce adipocyte differentiation in vitro. Using targeted mutagenesis of the mouse germline,
we show that E2F repression-deficient C/EBPα alleles failed to support adipocyte and
granulocyte differentiation in vivo. These results indicate that E2F repression by C/EBPα is
critical for its ability to induce terminal differentiation, and thus provide genetic evidence that
direct cell cycle control by a mammalian lineage-instructive transcription factor couples cellular
growth arrest and differentiation.
Article Outline
Introduction
Results
C/EBPα TE-I Is Required for C/EBPα-Mediated Adipocyte Differentiation, Growth Suppression
and E2F Inhibition
Conserved Non-DNA Binding Residues in the C/EBPα Basic Region Are Required for E2F
Repression and Adipogenesis
Ectopic E2F1 Activity Blocks Adipogenesis In Vitro
E2F1 Repression-Deficient C/EBPα Alleles Do Not Affect Liver Function In Vivo
E2F Repression-Deficient C/EBPα Alleles Cause Adipose Hypoplasia and Myeloid Dysplasia In
Vivo
Discussion
The Role of E2F Repression in C/EBPα-Mediated Growth and Differentiation
Tissue-Specific Requirement for E2F Repression by C/EBPα
Mechanism of C/EBPα-E2F Antagonism
Experimental Procedures
DNA Constructs
Targeting Constructs
Tissue Culture, Retroviral Infection, and Transfection
Western Blotting
GST Pull Down
Generation of C/EBPα Knockin Mice
Histology of Knockin Mice
Flow Cytometry
Electrophoretic Mobility Shift Assay
RNA Preparation and Northern Blotting
Acknowledgements
References
2 Kinetic properties of pig (Sus scrofa domestica) and bovine (Bos

4 taurus) D-fructose-1,6-bisphosphate 1-phosphohydrolase
(F1,6BPase): Liver-like isozymes in mammalian lung tissue Original
Research Article
Comparative Biochemistry and Physiology Part B: Biochemistry and
Molecular Biology, Volume 127, Issue 1, 1 September 2000, Pages 123-
134
Dariusz Rakus, Krzysztof Skalecki, Andrzej Dzugaj
Abstract
F1,6BPases from porcine and bovine lung were isolated and their kinetic properties were
determined. Ks, Kis and β were determined assuming partial-noncompetitive inhibition (simple
intersecting hyperbolic noncompetitive inhibition) of the enzyme by the substrate. Values for Ks
were 4.1 and 4.4 μM for porcine and bovine F1,6BPase, respectively and values for β were close
to 0.55 in both cases. Kis were 9 and 15 μM for porcine and bovine F1,6BPase, respectively. I0.5
for AMP were determined as 7 μM for pig enzyme and 14 μM for F1,6BPase from bovine lung.
The enzymes were inhibited by F2,6BP with Ki’s of 0.19 and 0.21 μM for porcine and bovine
enzymes, respectively. In the presence of AMP concentration equal to I0.5, the Ki values for pig
and bovine enzymes were 0.07 and 0.09 μM, respectively. The levels of F2,6BP, AMP and
antioxidant enzymes activities in pig and bovine lung tissues were also determined. The cDNA
coding sequence of pig lung F1,6BPase1 showed a high homology with pig liver enzyme,
differing only in four positions (G/C-63, T/A-808, G/C-884 and T/A-1005) resulting in a single
amino acid substitution (Gly-295 for Ala-295). It is hypothesized that the lung F1,6BPase
participates in gluconeogenesis, surfactant synthesis and antioxidant reactions.
Article Outline
1. Introduction
2.1. Materials
2.2. Methods
2.2.1. Enzyme assays
2.2.2. Metabolites
2.2.2.1. F2,6BP concentration in lung tissue
2.2.2.2. AMP concentration in lung tissue
2.2.3. F1,6BPase purification and SDS-PAGE
2.2.4. Kinetic investigation
2.2.5. Antibody production and Western blot analysis
2.2.6. Isolation of mRNA for F1,6BPase and nucleotide sequence analysis
3. Results and discussion
3.1. F1,6BPase purification and SDS-PAGE
3.2. Kinetic parameters of lung and liver F1,6BPases
3.3. Western blot analysis
3.4. Nucleotide sequence
3.5. Lung F1,6BPase physiological role
3.6. Activities of antioxidant enzymes (AOE)
References
2 Chapter 1 Regulation of Metabolism by Nuclear Hormone

5 Receptors Review Article
Progress in Molecular Biology and Translational Science, Volume 87,
2009, Pages 1-51
Huey-Jing Huang, Ira G. Schulman
The worldwide epidemic of metabolic disease indicates that a better understanding of the
pathways contributing to the pathogenesis of this constellation of diseases need to be
determined. Nuclear hormone receptors comprise a superfamily of ligand-activated transcription
factors that control development, differentiation, and metabolism. Over the last 15 years a
growing number of nuclear receptors have been identified that coordinate genetic networks
regulating lipid metabolism and energy utilization. Several of these receptors directly sample the
levels of metabolic intermediates and use this information to regulate the synthesis, transport,
and breakdown of the metabolite of interest. In contrast, other family members sense metabolic
activity via the presence or absence of interacting proteins. The ability of these nuclear receptors
to impact metabolism and inflammation will be discussed and the potential of each receptor
subfamily to serve as drug targets for metabolic disease will be highlighted.
Article Outline
I. Introduction
II. The PPARs
A. PPARα
B. PPARγ
C. PPARδ
D. PPARs and Atherosclerosis
E. PPARs and Inflammation
III. LXR
A. Regulation of Hepatic Lipid Metabolism by LXR
B. Regulation of Reverse Cholesterol Transport by LXR
C. LXR and Atherosclerosis
D. LXR and Inflammation
E. LXR and Diabetes
F. Therapeutic Potential of LXR Ligands
IV. FXR
A. FXR and the Control of Bile Metabolism
B. Gallstones, Cholestasis, and Bacterial Growth
C. FXR and Lipid Metabolism
D. FXR and Atherosclerosis
E. FXR and Diabetes
F. Control of Liver Regeneration and Tumorigenesis by FXR
G. Therapeutic Potential of FXR Ligands
V. RORα
A. Regulation of Lipid Metabolism by RORs
B. Role of RORs in Circadian Rhythm Control and Links to Metabolism
C. RORs and Inflammation
D. Therapeutic Potential of RORα Ligands
VI. ERRα
A. ERRα and the PGC-1α Pathway
B. ERRα and Diabetes
C. ERRα in Adipose and Intestine
D. ERRα and Cancer
E. Therapeutic Potential of ERRα Ligands
VII. Summary
References
2 The antimicrobial activity of C-reactive protein Review Article

6 Microbes and Infection, Volume 4, Issue 2, February 2002, Pages 201-
205
Alexander J. Szalai
Abstract
Recent studies in transgenic mice confirmed that C-reactive protein is protective against
microbial pathogens. This is consistent with its ability in vitro to bind microbes, activate the
complement classical pathway, and engage FcγRI and FcγRII. However, in transgenic mice
protection also requires the alternative pathway of complement, and FcγRI is dispensable.
Article Outline
1. CRP binds to pathogenic microbes
2. CRP has antimicrobial activity in vitro
3. CRP has antimicrobial activity in vivo
4. Mechanisms of CRP-mediated protection in vivo
5. Conclusions
References
2 Rat lung polychlorinated biphenyl-binding protein: Effect of

7 glucocorticoids on the expression of the clara cell-specific protein
during fetal development Original Research Article
Archives of Biochemistry and Biophysics, Volume 296, Issue 1, July
1992, Pages 302-307
Magnus Nord, Olof Andersson, Mikael Brönnegård, Johan Lund
Abstract
Certain metabolites of polychlorinated biphenyls (PCBs) are retained in the Clara cells and in the
airway lumen of rodent lung due to their interaction with a secretory 13-kDa protein. The
expression of this Clara cellspecific, PCB-binding protein (PCB-BP) during the fetal development
of the rat lung was studied by means of ligand binding and a monospecific antiserum. The PCB-
BP and specific 4,4′-bis([3H]methylsulfonyl)-2,2′,5,5′-tetrachlorobiphenyl binding was first
detected on gestational Day 19 and subsequently the levels of PCB-BP and specific ligand
binding increased as a function of gestational age. The start site of transcription for the rat PCB-
BP gene was determined by primer extension analysis and the information thus obtained was
used to develop a quantitative assay for the corresponding mRNA based on solution
hybridization and S1 nuclease mapping. The appearance of PCB-BP mRNA during fetal lung
development preceded the detection of immunoreactive protein and ligand binding by 1 day. By
Day 21, the level of PCB-BP mRNA was 15 ng/100 μg total lung RNA which is approximately
30–40% of adult levels. In utero exposure to the synthetic glucocorticoid betamethasone was
shown to increase specific 4,4′-bis([3H]methylsulfonyl) 2,2′,5,5′-tetrachlorobiphenyl binding, PCB-
BP protein, and PCB-BP mRNA if administered from gestational Day 18 and onward. By Days
21–22, glucocorticoid treatment resulted in a two- to threefold increase in the levels of specific
ligand binding, immunoreactivity, and mRNA, i.e., to approximately adult levels.
Article Outline
• References
2 Chapter 9 Protein Arginine Methyltransferases: Nuclear Receptor

8 Coregulators and Beyond Review Article
Progress in Molecular Biology and Translational Science, Volume 87,
2009, Pages 299-342
Peter Kuhn, Wei Xu
Protein arginine methyltransferases (PRMTs) are a family of enzymes that play a crucial role in
diverse cellular functions. Several PRMTs have been associated with gene expression
regulation, in which PRMTs act as histone methyltransferases, secondary coregulators of
transcription, or facilitate mRNA splicing and stability. Additional functions include modulation of
protein localization, ribosomal assembly, and signal transduction. At the organismal level, several
PRMTs appear to be important for development and may play an important role in cancer. The
relationships between their cellular and organismal functions are poorly understood; at least in
part due to the large body of enzymatic substrates for PRMTs and their transcriptional targets
that remain to be determined. Specific PRMT inhibitors have been developed in recent years,
which should help to shed light on their diverse biological roles. Connecting PRMT cellular
functions with their global effects on an organism will facilitate development of novel treatments
for human diseases.
Article Outline
I. Introduction
II. Enzymatic Activity of PRMTs
A. PRMTs Catalyzing Asymmetric Dimethylation (Type I)
B. PRMTs Catalyzing Symmetric Dimethylation (Type II)
C. PRMTs Without Identified Activity
D. Distributive Versus Processive Mechanism
E. Substrate Specificity and Regulation
F. Posttranslational Regulation of PRMTs
III. PRMTs in Transcriptional Regulation
A. PRMTs as Histone Methyltransferases
1. Histone Modification Catalyzed by Type I PRMTs
2. Histone Modification Catalyzed by Type II PRMTs
3. Histone Arginine Demethylation
B. PRMTs Involved in Nuclear Receptor Regulation
1. CARM1 as a Model Coactivator for Nuclear Receptor Transcription
2. Coactivators Methylated by CARM1
3. The Nonsubstrate CARM1 Interacting Proteins
4. Other PRMTs–Nuclear Receptor Interactions
C. PRMTs Regulate Transcription Mediated by Other Transcription Factors
1. PRMT1
2. CARM1
3. PRMT5
D. Interplay of PRMTs During Transcriptional Regulation
1. p53
2. NF-κB
3. E2Fs
E. PRMTs in Transcription Elongation
IV. PRMTs in Posttranscriptional Regulation
V. Structural Analysis of PRMTs
VI. Small Molecule Inhibitors for PRMTs
VII. Biological Functions of PRMTs
A. PRMTs in Differentiation and Development
1. PRMTs in Muscle Differentiation
2. PRMTs in Precursor Maintenance
3. PRMTs in Development—What We have Learned from Mouse Models
B. PRMTs in Cancer
C. PRMTs in Viral Infection and Immune Response
D. PRMTs in Metabolism
1. PRMTs in Glucose Metabolism
2. PRMTs in Adipogenesis
E. PRMTs and DNA Methylation
F. PRMTs and DNA Repair
G. PRMTs and Chromatin Domains
VIII. Concluding Remarks
Acknowledgements
References
2 Farnesyl diphosphate synthase localizes to the cytoplasm of

9 Trypanosoma cruzi and T. brucei
Experimental Parasitology, Volume 119, Issue 2, June 2008, Pages
308-312
Marcela Ferella, Zhu-Hong Li, Björn Andersson, Roberto Docampo
Abstract
The farnesyl diphosphate synthase (FPPS) has previously been characterized in trypanosomes
as an essential enzyme for their survival and as the target for bisphosphonates, drugs that are
effective both in vitro and in vivo against these parasites. Enzymes from the isoprenoid pathway
have been assigned to different compartments in eukaryotes, including trypanosomatids. We
here report that FPPS localizes to the cytoplasm of both Trypanosoma cruzi and T. brucei, and is
not present in other organelles such as the mitochondria and glycosomes.
Article Outline
1. Introduction
2.1. Cell cultures
2.2. Digitonin permeabilization assay
2.3. Enzymatic activities
2.4. Western blot analysis
2.5. Immunofluorescence microscopy
3. Results
3.1. Permeabilization assays and Western blot analysis
3.2. Immunofluorescence microscopy
4. Discussion
Acknowledgements
Appendix A. Supplementary data
References
3 Photosynthesis
0 Plant Biochemistry, 1997, Pages 49-110
J.R. Bowyer, R.C. Leegood
Summary
Photosynthesis is the process by which organisms convert light energy into chemical energy in
the form of reducing power (as NADPH or NADH) and ATP, and use these chemicals to drive
carbon dioxide fixation and reduction to produce sugars. In oxygenic photosynthetic organisms,
including higher plants, the source of reducing equivalents is H2O, releasing O2 as a by-product.
The overall reaction of oxygenic photosynthesis can be represented as: CO2+2H2O→(CH2O)
+H2O+O2 This process is responsible for producing virtually all the O2 in the atmosphere and for
fixing about 1011 tons of carbon from CO2 into organic compounds annually.
3 The hepatocyte nuclear factor-3/forkhead transcription regulatory
1 family in development, inflammation, and neoplasia Review Article
Critical Reviews in Oncology/Hematology, Volume 20, Issues 1-2,
August 1995, Pages 129-140
Robert Hromas, Robert Costa
Abstract
HNF-3/FKH genes are a large family of transcriptional activators. They are expressed in specific
developmental and tissue patterns. Indeed, several of them are known to be essential for normal
development (e.g. Dfkh and slp-1,2). Mutation within one of these genes produces mutant fruitfly
embryos that are unable to survive. This family shares conserved DNA binding and
transcriptional activation domains. The DNA binding domain has been crystallized, and its
structure determined. Although it has resemblance to helices of homeodomains and H5 histones,
it represents a new DNA binding motif, which has been called the ‘winged helix,’, because it
contains additional interactive peptide regions called termed wings. Subtle amino acid variations
in a region adjacent to the DNA recognition helix influence the recognition specificity of each
HNF-3/FKH protein and therefore confer selectivity in promoter regulation. Members of this
family are important in regulating the inflammatory response of the liver (the three HNF-3 genes).
In addition, several members may be important in blood cell development (H3 and 5-3). Finally,
two of these genes have been found to produce neoplasia (qin and FKHR). As investigation
progresses, the mechanism by which these genes regulate development, inflammation and
neoplasia will become more clear.
Article Outline
• References
3 Protein engineering
2 Current Opinion in Biotechnology, Volume 4, Issue 4, August 1993,
Pages 491-512
Abstract
3 The mitochondrial FAD-dependent glycerol-3-phosphate

3 dehydrogenase of Trypanosomatidae and the glycosomal redox
balance of insect stages of Trypanosoma brucei and Leishmania
spp. Original Research Article
Molecular and Biochemical Parasitology, Volume 149, Issue 2, October
2006, Pages 155-169
Daniel G. Guerra, Anabelle Decottignies, Barbara M. Bakker, Paul A.M.
Michels
Abstract
The genes for the mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase were
identified in Trypanosoma brucei and Leishmania major genomes. We have expressed the L.
major gene in Saccharomyces cerevisiae and confirmed the subcellular localization and activity
of the produced enzyme. Using cultured T. brucei procyclic and Leishmania mexicana
promastigote cells with a permeabilized plasma membrane and containing intact glycosomes, it
was shown that dihydroxyacetone phosphate is converted into pyruvate, and stimulates oxygen
consumption, indicating that all components of the glycerol 3-phosphate/dihydoxyacetone
phosphate shuttle between glycosomes and mitochondrion are present in these insect stages of
both organisms. A computer model has been prepared for the energy and carbohydrate
metabolism of these cells. It was used in an elementary mode analysis to get insight into the
metabolic role of the shuttle in these insect-stage parasites. Our analysis suggests that the
shuttle fulfils important roles for these organisms, albeit different from its well-known function in
the T. brucei bloodstream form. It allows (1) a high yield of further metabolizable glycolytic
products by decreasing the need to produce a secreted end product of glycosomal metabolism,
succinate; (2) the consumption of glycerol and glycerol 3-phosphate derived from lipids; and (3)
to keep the redox balance of the glycosome finely tuned due to a highly flexible and redundant
system.
Article Outline
1. Introduction
2.1. Sequence analysis
2.2. Expression of putative FAD-GPDH
2.3. Cloning of the L. major GUT2 homologue and its expression in yeast
2.4. FAD-dependent glycerol-3-phosphate dehydrogenase activity
2.5. Fluorescence microscopy
2.6. Digitonin cell permeabilization
2.7. Stoichiometry analysis
3. Results
3.1. Sequence analysis
3.2. Subcellular localization of FAD-GPDH enzymes
3.3. Enzymatic activity of FAD-GPDH
3.4. Experiments with permeabilized T. brucei cells
3.5. Stoichiometry analysis
4. Discussion
Acknowledgements
References
3 Peroxisome proliferator-activated receptors: insight into multiple

4 cellular functions Original Research Article
Mutation Research/Fundamental and Molecular Mechanisms of
Mutagenesis, Volume 448, Issue 2, 17 March 2000, Pages 121-138
Pascal Escher, Walter Wahli
Abstract
Peroxisome proliferator-activated receptors, PPARs, (NR1C) are nuclear hormone receptors
implicated in energy homeostasis. Upon activation, these ligand-inducible transcription factors
stimulate gene expression by binding to the promoter of target genes. The different structural
domains of PPARs are presented in terms of activation mechanisms, namely ligand binding,
phosphorylation, and cofactor interaction. The specificity of ligands, such as fatty acids,
eicosanoids, fibrates and thiazolidinediones (TZD), is described for each of the three PPAR
isotypes, α (NR1C1), β (NR1C2) and γ (NR1C3), so as the differential tissue distribution of these
isotypes. Finally, general and specific functions of the PPAR isotypes are discussed, namely
their implication in the control of inflammatory responses, cell proliferation and differentiation, the
roles of PPARα in fatty acid catabolism and of PPARγ in adipogenesis.
Article Outline
1. Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors
2. Genomic organization
3. Structure and functions of PPARs
3.1. A/B domain
3.2. DNA-binding domain
3.3. Ligand-binding domain
3.4. Cofactor recruitment
4. Ligand-specificity of PPAR isotypes
5. Tissue-specific expression of PPARs
6. Physiological roles
6.1. PPARα in lipid catabolism
6.2. PPARα and hepatocarcinogenesis
6.3. PPARβ in development
6.4. PPARγ in adipogenesis
6.5. PPARγ in cell differentiation and cell-cycle withdrawal
6.6. PPARs in inflammation
7. Conclusion
Acknowledgements
References
3 Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)

5 Ligands and Their Therapeutic Utility Review Article
Progress in Medicinal Chemistry, Volume 42, 2004, Pages 1-53
Brad R Henke
Excerpt | Figures/Tables | References
Click here for a PDF Excerpt.
Article Outline
1. Introduction
2. Biochemical evaluation of PPAR activation
3. PPARγ ligands
3.1. Natural ligands
3.2. Synthetic ligands
3.2.1. Selective PPARγ agonists
3.2.2. PPARα/γ dual agonists
3.2.3. PPARγ/δ dual agonists and PPARα/γ/δ pan-agonists
3.2.4. PPARγ antagonists, partial agonists, and modulators
4. Protein structure of PPARγ
5. Therapeutic utility of PPARγ ligands
5.1. Diabetes and insulin resistance
5.2. Dyslipidemia
5.3. Inflammation and atherosclerosis
5.4. Hypertension
5.5. Alzheimer's disease
5.6. Cancer
6. Summary and perspectives
Acknowledgements
References
3 Solute Transport, Energy Consumption, and Production in the

6 Kidney
Seldin and Giebisch's The Kidney (Fourth Edition), 2008, Pages 185-
209
Takashi Sekine, Hiroki Miyazaki, Hitoshi Endou
Summary
The kidney must reabsorb more than 99% of approximately 180 liters of water and 25,000
mmoles of Na+ daily. To do this, the kidney consumes a large amount of energy. Although the
kidney is only 0.5% of total body weight, it utilizes approximately 7% of the oxygen consumed by
the body (272). In fact, the kidney is second only to the heart in terms of the rate of energy
consumption (272). In this chapter, we describe the energy consumption and production
processes in the kidney, along with their mutual relationships. We also refer to the
pathophysiological states in which renal energy production is inhibited.
3 8 Molecular Aspects of Pancreatic Peptides Original Research Article

7 Fish Physiology, Volume 13, 1994, Pages 225-271
Stephen J. Duguay, Thomas P. Mommsen
Excerpt | References
3 Biogenesis of peroxisomes and glycosomes: trypanosomatid

8 glycosome assembly is a promising new drug target Review Article
FEMS Microbiology Reviews, Volume 28, Issue 5, November 2004,
Pages 603-643
Juliette Moyersoen, Jungwoo Choe, Erkang Fan, Wim G.J. Hol, Paul
A.M. Michels
Close preview | Related articles | Related reference work articles
Abstract | Figures/Tables
Abstract
In trypanosomatids (Trypanosoma and Leishmania), protozoa responsible for serious diseases of
mankind in tropical and subtropical countries, core carbohydrate metabolism including glycolysis
is compartmentalized in peculiar peroxisomes called glycosomes. Proper biogenesis of these
organelles and the correct sequestering of glycolytic enzymes are essential to these parasites.
Biogenesis of glycosomes in trypanosomatids and that of peroxisomes in other eukaryotes,
including the human host, occur via homologous processes involving proteins called peroxins,
which exert their function through multiple, transient interactions with each other. Decreased
expression of peroxins leads to death of trypanosomes. Peroxins show only a low level of
sequence conservation. Therefore, it seems feasible to design compounds that will prevent
interactions of proteins involved in biogenesis of trypanosomatid glycosomes without interfering
with peroxisome formation in the human host cells. Such compounds would be suitable as lead
drugs against trypanosomatid-borne diseases.
Article Outline
1. Introduction
2. Glycolysis in trypanosomatids
3. Glycosomes, structure and function
4. Proper compartmentation of glycosomal enzymes and intact glycosomes are vital to
trypanosomes
5. Overview of peroxisome biogenesis
5.1. Import of matrix proteins; receptor recognition
5.2. The docking complex for import of matrix proteins
5.3. Import of matrix proteins; cargo–receptor complex translocation and receptor recycling
5.4. Receptor recycling and the ‘extended shuttle’ model for the import of matrix proteins
5.5. Three models for the translocation mechanism of matrix proteins
5.6. Preimplex hypothesis for the import of matrix proteins
5.7. Insertion of peroxisomal membrane proteins
5.8. Proliferation of peroxisomes and the formation of their membrane
5.9. Growth and division model versus de novo formation model
5.10. A role for the ER in peroxisomal membrane formation and insertion of peroxisomal
membrane proteins?
6. Aspects of glycosome biogenesis
6.1. Targeting and import of glycosomal matrix proteins
6.2. Peroxins involved in glycosome biogenesis
6.3. Protein interactions in glycosome biogenesis and possibilities for drug design
6.3.1. PTS1 protein–PEX5 interaction
6.3.2. PTS2 protein–PEX7 interaction
6.3.3. PEX5–PEX14 interaction
6.3.4. Putative interactions of I-PTS proteins
7. Feasibility to target transient protein–protein interactions
8. Conclusions
Acknowledgements
References
3 Pharmaceutical applications
9 Current Opinion in Biotechnology, Volume 4, Issue 6, December 1993,
Pages 785-817
Abstract
4 SIMD Abstracts Issue 2005

0 Molecular Genetics and Metabolism, Volume 84, Issue 3, March 2005,
Pages 193-242
Abstract
4 Subject index
1 Advances in Drug Research, Volume 26, 1995, Pages 259-272
Excerpt
4 Keyword index to volumes 400–420

2 FEBS Letters, Index to Volumes 400-420, 1997, Pages 81-115
Abstract
4 CAR and PXR: The xenobiotic-sensing receptors Review Article

3 Steroids, Volume 72, Issue 3, March 2007, Pages 231-246
Yoav E. Timsit, Masahiko Negishi
Abstract
The xenobiotic receptors CAR and PXR constitute two important members of the NR1I nuclear
receptor family. They function as sensors of toxic byproducts derived from endogenous
metabolism and of exogenous chemicals, in order to enhance their elimination. This unique
function of CAR and PXR sets them apart from the steroid hormone receptors. In contrast, the
steroid receptors, exemplified by the estrogen receptor (ER) and glucocorticoid receptor (GR),
are the sensors that tightly monitor and respond to changes in circulating steroid hormone levels
to maintain body homeostasis. This divergence of the chemical- and steroid-sensing functions
has evolved to ensure the fidelity of the steroid hormone endocrine regulation while allowing
development of metabolic elimination pathways for xenobiotics. The development of the
xenobiotic receptors CAR and PXR also reflect the increasing complexity of metabolism in higher
organisms, which necessitate novel mechanisms for handling and eliminating metabolic by-
products and foreign compounds from the body. The purpose of this review is to discuss
similarities and differences between the xenobiotic receptors CAR and PXR with the prototypical
steroid hormone receptors ER and GR. Interesting differences in structure explain in part the
divergence in function and activation mechanisms of CAR/PXR from ER/GR. In addition, the
physiological roles of CAR and PXR will be reviewed, with discussion of interactions of CAR and
PXR with endocrine signaling pathways.
Article Outline
1. Introduction
2. The xenobiotic receptors: CAR and PXR
2.1. Functions
2.1.1. Xenobiotic and endobiotic metabolism
2.1.2. Role in gluconeogenesis and bile acid homeostasis
2.2. Ligand promiscuity and species differences
2.3. Mechanisms of activation
2.3.1. CAR
2.3.1.1. Overview
2.3.1.2. Nuclear translocation
2.3.2. PXR
2.3.2.1. Overview
2.3.2.2. Nuclear translocation
2.4. Structural aspects of CAR and PXR
2.4.1. CAR
2.4.2. PXR
3. Comparison of CAR/PXR to ER/GR
3.1. Structure
3.2. Intracellular trafficking
3.3. Protein phosphorylation
4. Indirect role of endocrine factors in CAR/PXR signaling
4.1. Steroid hormones
4.2. Growth factors
5. Concluding remarks and future directions
Acknowledgements
References
4 Subject index
4 Trends in Biochemical Sciences, Volume 8, Issue 12, December 1983,
Pages v-viii
Abstract
4 Reviews: current topicsrole of nuclear receptors in the regulation

5 of gene expression by dietary fatty acids (review) Review Article
The Journal of Nutritional Biochemistry, Volume 14, Issue 10, October
2003, Pages 554-567
Seher A. Khan, John P. Vanden Heuvel
Abstract
Long chain fatty acids, derived either from endogenous metabolism or by nutritional sources play
significant roles in important biological processes of membrane structure, production of
biologically active compounds, and participation in cellular signaling processes. Recently, the
structure of dietary fatty acids has become an important issue in human health because ingestion
of saturated fats (containing triglycerides composed of saturated fatty acids) is considered
harmful, while unsaturated fats are viewed as beneficial. It is important to note that the molecular
reason for this dichotomy still remains elusive. Since fatty acids are important players in
development of pathology of cardiovascular and endocrine system, understanding the key
molecular targets of fatty acids, in particular those that discriminate between saturated and
unsaturated fats, is much needed. Recently, insights have been gained on several fatty acid-
activated nuclear receptors involved in gene expression. In other words, we can now envision
long chain fatty acids as regulators of signal transduction processes and gene regulation, which
in turn will dictate their roles in health and disease. In this review, we will discuss fatty acid-
mediated regulation of nuclear receptors. We will focus on peroxisome proliferators-activated
receptors (PPARs), liver X receptors (LXR), retinoid X receptors (RXRs), and Hepatocyte
Nuclear Factor alpha (HNF-4α), all of which play pivotal roles in dietary fatty acid-mediated
effects. Also, the regulation of gene expression by Conjugated Linoleic Acids (CLA), a family of
dienoic fatty acids with a variety of beneficial effects, will be discussed.
Keywords: Fatty acid; Nuclear receptor; Gene; Transcription
Article Outline
1. Dietary fatty acids and health
2. Nuclear receptors
2.1. Functional Domains
2.2. Basic mechanism of action
2.3. Ligands and activators
2.4. Reverse endocrinology
3. Peroxisome proliferator-activated receptors (PPARs)
3.1. PPAR subtypes and expression
3.2. Endogenous PPAR ligands
3.3. Target genes
3.4. Physiological role
3.5. Lxr
3.6. Physiological roles
3.6.1. Central nervous system
3.6.2. Diabetes
3.6.3. Skeletal muscle
3.6.4. Atherosclerosis
3.7. Hepatocyte nuclear factor (HNF-4α)
3.8. Rxr
3.9. Conjugated linoleic acids as ligands for NRs
4. Conclusions
Acknowledgements
References
4 Subject index
6 Advances in Enzyme Regulation, Volume 31, 1991, Pages 465-483
Abstract
4 Index
7 Handbook of Cell Signaling (Second Edition), 2010, Pages 2983-3047
Excerpt
4 Neuropeptide : Y. Karolinska Institute Nobel Conference Series

8 Edited by V. Mutt, K. Fuxe, T. Hokfelt and J.M. Lundberg. Published
1989 by Raven Press, New York. No. of pages: 377. ISBN: 0-88167-
556-3. Retail price: US$156.50
Journal of Steroid Biochemistry, Volume 35, Issues 3-4, March 1990,
Pages 515-516
Abstract
4 Peroxisome proliferator-activated receptor gamma (PPARγ) and its

9 ligands: A review Original Research Article
Domestic Animal Endocrinology, Volume 22, Issue 1, March 2002,
Pages 1-23
Karen L. Houseknecht, Bridget M. Cole, Pamela J. Steele
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of a class of nuclear
hormone receptors intimately involved in the regulation of expression of myriad genes that
regulate energy metabolism, cell differentiation, apoptosis and inflammation. Although originally
discovered as a pivotal regulator of adipocyte differentiation, the roles that this transcription
factor play in physiology and pathophysiology continue to grow as researchers discover its
influence in the function of many cell types. This review highlights the roles that PPARγ play in
the regulation of gene expression associated with normal cell physiology as well as the
pathophysiology of multiple diseases including obesity, diabetes and cancer. Additionally,
naturally occurring and pharmaceutical ligands for the receptor as well as the potential role of
PPARγ as the receptor responsible for fatty acid-induced effects on gene expression will be
described.
Article Outline
1. Introduction
2. PPAR: key regulators of gene transcription
3. PPARγ ligands
4. PPARγ function in cell differentiation
4.1. PPARγ: a pivotal regulator of adipocyte differentiation
5. Regulation of PPARγ gene expression
6. Nutritional regulation of gene expression: PPARγ as a fatty acid receptor
7. Role of PPARγ in nutritional regulation of gene expression
8. Role of PPARγ in the pathophysiology of diabetes, cancer and inflammation
9. PPARγ ligands are insulin sensitizers
10. PPAR gamma and beta cell function
11. Mutations in hPPARγ gene impact insulin action
12. PPARγ in inflammation
13. PPARγ and cancer
14. Summary
References
5 Subject Index
0 Progress in Medicinal Chemistry, Volume 30, 1993, Pages 379-387
Excerpt
5 PAT proteins, an ancient family of lipid droplet proteins that

1 regulate cellular lipid stores Review Article
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of
Lipids, Volume 1791, Issue 6, June 2009, Pages 419-440
Perry E. Bickel, John T. Tansey, Michael A. Welte
Abstract
The PAT family of lipid droplet proteins includes 5 members in mammals: perilipin, adipose
differentiation-related protein (ADRP), tail-interacting protein of 47 kDa (TIP47), S3–12, and
OXPAT. Members of this family are also present in evolutionarily distant organisms, including
insects, slime molds and fungi. All PAT proteins share sequence similarity and the ability to bind
intracellular lipid droplets, either constitutively or in response to metabolic stimuli, such as
increased lipid flux into or out of lipid droplets. Positioned at the lipid droplet surface, PAT
proteins manage access of other proteins (lipases) to the lipid esters within the lipid droplet core
and can interact with cellular machinery important for lipid droplet biogenesis. Genetic variations
in the gene for the best-characterized of the mammalian PAT proteins, perilipin, have been
associated with metabolic phenotypes, including type 2 diabetes mellitus and obesity. In this
review, we discuss how the PAT proteins regulate cellular lipid metabolism both in mammals and
in model organisms.
Article Outline
1. Introduction
1.1. Lipid droplets and cellular lipid metabolism
1.2. Perilipin and the PAT family of lipid droplet proteins
2. Perilipin
2.1. Perilipin expression
2.2. Perilipin is polyphosphorylated by protein kinase A
2.3. The functions of perilipin in cellular TAG metabolism
2.4. The role of perilipin in physiology
2.5. Roles of perilipins in human health
2.6. Disease states may affect perilipin expression
2.7. Perilipin may not localize exclusively to the surface of lipid storage droplets
3. ADRP/adipophilin/ADFP/ADPH
3.1. ADRP and adipogenesis
3.2. ADRP in perilipin-null mice
3.3. Studies of ADRP function in cellular lipid metabolism
3.4. Mouse models of ADRP deficiency
3.5. ADRP protein levels in human skeletal muscle
3.6. Cell-based studies of ADRP and lipoprotein metabolism
3.7. ADRP and atherosclerosis
3.8. Regulation of ADRP expression and function
3.9. ADRP, the constitutive PAT protein for non-adipocytes
4. TIP47/PP17/M6PBP
4.1. TIP47, the first reported exchangeable lipid droplet protein
4.2. Other proposed roles for TIP47
4.3. TIP47, lipid droplets, and the eye
4.4. Functional studies of TIP47 using RNA interference
4.5. The structure of TIP47
5. S3–12 and MLDP/OXPAT/LSDP5
5.1. S3–12 and OXPAT, tandem genes with reciprocal expression
5.2. S3–12, TIP47, and ADRP in nascent lipid droplet biogenesis
5.3. S3–12 and the 11-mer repeats: a putative mechanism for lipid droplet binding
5.4. OXPAT, regulation by PPARs in mice and humans
5.5. OXPAT, functional studies in cells
6. Non-mammalian PAT proteins
6.1. LSD-1 and LSD-2 of Drosophila and other insects
6.1.1. Lipid metabolism in mammals and insects
6.1.2. PAT proteins of insects
6.1.3. Intracellular distribution of insect PAT proteins
6.1.3.1. LSD-1 and LSD-2 are lipid droplet proteins
6.1.3.2. Mechanisms of droplet targeting
6.1.3.3. Are LSD-1 and LSD-2 restricted to lipid droplets?
6.1.4. Lipid homeostasis
6.1.4.1. LSD-1 phosphorylation is linked to control of lipolysis
6.1.4.2. LSD-2 promotes storage of neutral lipids
6.1.4.3. LSD-2 and droplet biogenesis
6.1.4.4. LSD-2 and lipid homeostasis
6.1.5. Lipid droplet motion
6.1.5.1. PAT proteins and droplet motion
6.1.5.2. LSD-2 determines directionality of droplet motion
6.1.5.3. Parallels to mammals
6.2. Fatvg of Xenopus laevis
6.2.1. Fatvg mRNA is asymmetrically distributed
6.2.2. Fatvg is essential for normal embryogenesis
6.2.3. Relevance for mammalian biology
6.3. MPL1 of Metarhizium and related fungi
6.3.1. MPL1: a droplet protein involved in lipid metabolism
6.3.2. MPL1 as a virulence factor
6.4. Prospects for the study of mammalian PATs
7. Mammalian and non-mammalian PAT proteins, an ancient family for a fundamental need
Acknowledgements
References
5 The steroid/thyroid hormone receptor family and gene regulation :

2 Birkhauser Congress Reports-Life Sciences, Vol. 4. Edited by J.
Carlstedt-Duke, H. Eriksson and J.-A. Gustafsson. Published 1989
by Birkhauser Verlag, Basel. ISBN: 3-7643-2275-6. Price: SFR
84.00
Journal of Steroid Biochemistry, Volume 35, Issues 3-4, March 1990,
Page 515
Abstract
5 Nuclear receptors as drug targets for metabolic disease Review

3 Article
Advanced Drug Delivery Reviews, Volume 62, Issue 13, 30 October
2010, Pages 1307-1315
Ira G. Schulman
Abstract
Nuclear hormone receptors comprise a superfamily of ligand-activated transcription factors that
control development, differentiation, and homeostasis. Over the last 15 years a growing number
of nuclear receptors have been identified that coordinate genetic networks regulating lipid
metabolism and energy utilization. Several of these receptors directly sample the levels of
metabolic intermediates including fatty acids and cholesterol derivatives and use this information
to regulate the synthesis, transport, and breakdown of the metabolite of interest. In contrast,
other family members sense metabolic activity via the presence or absence of interacting
proteins. The ability of these nuclear receptors to impact metabolism will be discussed and the
challenges facing drug discovery efforts for this class of targets will be highlighted.
Article Outline
1. Introduction
2. The PPARs
2.1. PPARα
2.2. PPARγ
2.3. PPARδ
2.4. PPARs and inflammation
3. LXRs
3.1. Regulation of macrophage reverse cholesterol transport by LXR
3.2. LXR and atherosclerosis
3.3. Regulation of hepatic lipid metabolism by LXR
3.4. LXR and diabetes
4. Therapeutic potential of the metabolic nuclear receptors
Acknowledgements
References
5 Subject Index
4 Journal of Chromatography Library, Volume 61, 1999, Pages 895-936
Excerpt
5 FEBS Letters volumes 337–356 master subject index

5 FEBS Letters, Volume 356, Supplement 1, 1994, Pages 63-91
Abstract
5 Subject Index
6 Vitamins & Hormones, Volume 77, 2007, Pages 347-354
Excerpt
5 Gene-Specific Regulation by General Translation Factors Review

7 Article
Cell, Volume 108, Issue 4, 22 February 2002, Pages 545-556
Thomas E. Dever
Abstract
Protein synthesis is the ultimate step of gene expression and a key control point for regulation. In
particular, it enables cells to rapidly manipulate protein production without new mRNA synthesis,
processing, or export. Recent studies have enhanced our understanding of the translation
initiation process and helped elucidate how modifications of the general translational machinery
regulate gene-specific protein production.
Article Outline
• Main Text
• Overview of Translation Initiation
• mRNA Features Affect Translation Efficiency
• Factor Interactions Facilitate Initiation Complex Formation
• Alternate Translation Initiation Pathways
• Mechanisms of Gene-Specific and General Translational Control
• Regulation of Met-tRNAiMet Binding
• eIF2α Phosphorylation
• Short uORFs Sensitize Translation to the Level of eIF2α Phosphorylation
• GCN4
• ATF4
• C/EBP
• Are Other mRNAs with uORFs Regulated by eIF2α Phosphorylation?
• eIF2B Regulation
• Regulation of mRNA Binding
• 4E-BP Phosphorylation
• eIF4E Availability and Phosphorylation
• eIF4G Cleavage and Availability
• Concluding Remarks
• Acknowledgements
• References
5 MANGANESE
8 Encyclopedia of Human Nutrition, 2005, Pages 217-225
C. L. Keen, J. L. Ensunsa, B. Lönnerdal, S. Zidenberg-Cherr
Excerpt | Figures/Tables | References
Article Outline
• Chemical and Physical Properties
• Dietary Sources
• Analysis
• Physiological Role
• Tissue Concentrations
• Absorption, Transport, and Storage
• Metabolic Function and Essentiality
• Manganese Deficiency
• Manganese Toxicity
• Assessment of Manganese Status
• Further Reading

Supplementary Files
5 Towards a therapy for phosphomannomutase 2 deficiency, the

9 defect in CDG-Ia patients Review Article
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease,
Volume 1792, Issue 9, September 2009, Pages 835-840
Hudson H. Freeze
Abstract
Phosphomannomutase (PMM2, Mannose-6-P→ Mannose-1-P) deficiency is the most frequent
glycosylation disorder affecting the N-glycosylation pathway. There is no therapy for the
hundreds of patients who suffer from this disorder. This review describes previous attempts at
therapeutic interventions and introduces perspectives emerging from the drawing boards. Two
approaches aim to increase Mannose-1-P: small membrane permeable molecules that increase
the availability or/and metabolic flux of precursors into the impaired glycosylation pathway; and,
phosphomannomutase enhancement and/or replacement therapy. Glycosylation-deficient cell
and animal models are needed to determine which individual or combined approaches improve
glycosylation and may be suitable for preclinical evaluation.
Article Outline
1. Introduction
2. Metabolic pathways
3. Setting the stage for therapy: what is possible and practical?
4. Mannose supplements: simple but ineffective
5. Bypass the defect: membrane permeable mannose-1-P
6. Enzyme replacement therapy
7. Activate or stabilize PMM2
8. Increase mannose-6-P flux into glycosylation pathways
9. Future perspectives and challenges
10. Conclusions
Acknowledgements
References

59 articles found for: ALL(PEPCK crystallography)
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