INTRO TO METABOLISM
To survive
Basic metabolic requirements:
- synthesize everything our cells need
that is not supplied by our diet
- be able to protect our internal
environment from toxins and
changing conditions in our external
environment
convert fuels into energy
Chemical reactions
- Organized into multistep sequences
(pathways)
- Pathways intersect to form
integrated purposeful network of
chemical reactions
- collectively called metabolism
Basic pathways
fuel oxidative pathways : convert fuels
into energy
- Food are the fuels that supply us with
energy in the form of calories
- used for carrying out diverse func
fuel storage pathways : we store, can
be mobilized during periods when we
are not eating
biosynthetic pathways
detoxification or waste disposal
pathways
Metabolism
Interconversion of chemical compounds
- Reactions are necessary for
maintenance, growth and repro
Pathways taken by individual molecules,
their interrelationships
Mechanisms that regulate the flow of
metabolites thru the pathways
Metabolites: the participants in
metabolic reactions;
- Substrate
- Intermediate
- product
through four basic types of pathways:
fuel oxidative pathways
fuel storage and mobilization
pathways
biosynthetic pathways
detoxification or waste disposal
pathways
Categories of metabolic pathways
Anabolic: assembly of complex organic
molecules
- endothermic
Catabolic:degradation of complex
substances
- Oxidative
- Exothermic, producing ATP
Amphibolic : link between the 2 (CAC)
Catabolic rxns take place in the Mito
Anabolic rxns take place in the Cytosol
Electrons are shuttled through
mitochondria
Energy metabolism
Entirety of reactions
chemical reactions involved in energy
transformations
Bioenergetics : study of energy changes
that accompany biochemical reactions
Reactions are organized into metabolic
pathways
- transformation through a series of
steps, by a sequence of enzymes
Metabolism converts the fuel in the food
into energy
Energy the ability to do work
biosynthesis of cellular and extracellular
components
the transport of ions and organic
chemicals against concentration
gradients (osmotic work)
the conduction of electrical impulses in
the nervous system
the movement of cells and the whole
organism
Intermediary metabolism:
reactions concerned with storing and
generating metabolic energy and using
that energy in synthesis of compounds;
which food is metabolized and
converted into cellular components or
utilized
Not involving nucleic acid template
Information needed to specify reaction
is in the enzyme
Normal metabolism
Adaptation to starvation, exercise,
pregnancy, lactation
Abnormal FA
Nutritional deficiency - Substrate for gluconeogenesis
Enzyme deficiency - Odd chain FA yield propionyl CoA
Abnormal secretion of hormones, drugs - Glycerol
or toxins - FA (even C) and ketones cannot be
converted to glucose
Autotrophs - Acetyl CoA cannot be converted to
Synthesize their organic compounds glucose
from inorganic compound (CO2)
Heterotrophs Fates of nutrients
Synthesize organic compounds from Products of intestinal digestion
other organic compounds Absorbed into portal
- AA
3 Stages of metabolism - Glucose
Stage 1 Liver
- Reactions that convert polymeric - Glucose
metabolites (polysaccharides, - In excess of metabolic fuel
proteins) with their monomeric units - Glycogenesis
(monosaccharides or amino acids) - Lipogenesis
- breakdown of large macromolec to AA
simple subunits - Synthesis of plasma protein
Stage 2 - Excess AA deaminated, into urea
- Monomers are degraded to Skeletal muscles
intermediates: compounds not Glucose
identifiable as CHO, lipid or protein - Fuel
- breakdown of simple subunits to - Stores
acetyl coA accompanied by AA
production of limited amts of ATP and - Synthesis of muscle proteins
NADH (stores for gluconeogenesis)
Stage 3 Lipids
- Pathways that carry out ultimate Dietary TGL absorbed as
degradation to CO2, H2O, and NH3 chylomicrons
(CAC) - Undergo metabolism in circulation
- complete oxidation of acetyl coA to - Chylomicron remnants taken up by
H2O and CO2 accompanied by large liver
amts of ATP in mitochondrion Synthesis in adipose and liver
- Adipose TGL is main fuel reserve
Metabolic fuels are interconvertible - Lipolysis provide
CHO FA
- Excess can be transformed into FA, Glycerol for glucogenesis
TGL (adipose and liver) - Liver
Most AA (diet or tissues) VLDL from Synthesized TGL, FFA,
Glucogenic remnants
- Yield pyruvate or carbon Excess FA converted to ketones
intermediates for gluconeogenesis
- OAA is the primary substrate for Requirement for fuels is relatively
glconeogenesis constant
- Pyruvate + CO2 = OAA Metabolic fuel for most tissues : glucose
- Carbon intermediates = Tissues dependent on glucose:
OAA - Brain: largely dependent
Glucogenic and ketogenic - RBC : entirely dependent
- Phe, Tyr, Try, isoleucine Reserves
Ketogenic - TGL
- lysine and leucine - Glycogen (under control of insulin
and glucagon)
Control CARBOHYDRATES METABOLISM Fructose may enter the pathway and Energy balance when pyruvate enters
Enzymes Glycolysis directly phosphorylated to F-1-P mitochondrion
- Acvtivity CAC Bypassing regulated step produces Glyceraldehyde 3-P DH NADH x2= 6
- Level Glycogen more pyruvate than required for energy Phosphoglycerate kinase 1ATP x 2 = 2
Compartmentation Pentose phosphate pathway In liver and adipose : increases Pyruvate Kinase 1 ATP x 2 =2
Hormones gluconeogenesis lipogenesis Total = 10
Less investment (Hexokinase and PFK)
Where rxns occur Glucose: Then.. ATP 2
cytoplasm Is the primary energy source for the Cleavage of F1,6BP Net = 8
- glycolysis brain, skeletal muscle, and red blood Aldolase A (F-1-6BP aldolase)
- production of fa and aa cells - 3GAP Anaerobic
- PPP Deficiency can impair the brain and - DHAP - Pyruvate is reduced to lactate
- part of gluconeogenesis nervous system Triose Phosphate isomerase - Lactate DH
mitochondria Sources: - NADH NAD
- cac - diet Generation phase - energy balance: 2 NADH is
- fa oxidation - Production of glucose Oxidation of G-3-P reoxidized: 2ATP
- aa oxidation Oxidation of complex polymers G-3-P DH - Allows glycolysis to proceed w/o O2
- b-oxidation Degradation of strored glucose - Transfer of H to NAD - regenerates NAD for next cycle
- ketogenesis Synthesis of glucose from LA, AA, - Pi is added - Lactate : major product
- etc glycerol - 1,3-diPPG (DPG) - When lactate is end product: Net is 2
ER membranes 1st substrate ATP ATP
- TGL synthesis Glycolysis PPG kinase Tissues that produce lactate
Ribosomes Major path for glucose metabolism - ATP + 3-PP glycerate - RBC
- protein synthesis Aerobic or anaerobic Phosphoglycerate Mutase - Skeletal muscles
This makes the various rxns easier to 1 mol of glucose to 2 mol of pyruvate - 2-PPG Tissues that Normally get energy from
control because they occur in different In cytosol Dehydration of 2-DPG glycolysis and produce lactate
places Glu + 2ADP + 2Pi - 2 lactate + 2ATP Enolase - Brain
+ 2H2O - Inhibited by fluoride - GIT
Regulation of pathways is important to - H2O + PEP - Renal medulla
ensure appropriate supply of products Investment phase 2nd substrate ATP - Retina
from that pathway hexokinase Pyruvate kinase - skin
Control of key reactions (those that are Commits glucose - Pyruvate + ATP Tissues that oxidize lactate but produce
catalyzed by regulatory enzymes) Availability of glucose is controlled by under hypoxic conditions
- Appropriate supply of substrates transport of glucose Overall glycolysis - Liver, kidney, heart
Regulation of reactions 1st investment glucose + 2ATP + 2ADP + 2PO4 + Yeast:
- Enzymes (Allosteric modifiers) PFK-1 2NAD Decarboxylation
- Hormones 1,6- fructose biphosphate - (Pyruvate decarboxylase)
Most impoprtant control; rate limiting 2 pyruvate + 2NAH + 2H20 + 4ATP reduction by NADH
Goal of regulation: step in glycolysis - (alcohol DH)
Energy and products meet the needs of Functionally irreversible Pyruvate Kinase step (form pyruvate)
the cell 2nd investment generates net gain of 2 mol of ATP RBC
Means of communication system Cells must produce 1 or more net ATP - Alternate path:bypass
between cells to coordinate the Hexokinase: per glucose to survive and grow - Phosphoglycerate kinase
functions - Irreversible - Form 2,3-BPG
- Allosterically inhibited by product enzymes activator inhibitor - Phosphoglycerate mutase
Regulatory signals that influence the Glucokinase (liver) hexokinase AMP/ADP G6P - Binds to Hb and decrease O2 affinity
regulatory signals from the cell - For glycogenesis, lipogenesis PFK AMP/ADP ATP - No ATP
Hormones G-6-P : F2, 6bP Citrate
NS - Glycolysis PK AMP/ADP ATP Regulation of glycolysis
Availability of nutrients - Gluconeogenesis F1,6bbP Acetyl coA three regulated enzymes
Regulatory signals from the cell may be - PPP Alanine Hexokinase
influenced by - Glycogenesis - Inhibited by G-6-P
Nutrients, substrates - glycogenolysis Phosphofructokinase
Product inhibition G-6-P is converted to F 6-P by - ATP and citrate
Allosteric inhibitors or activators phosphohexose isomerase pyruvate kinase - By ATP
To meet major cellular needs: Deficiency and inhibition of Pyruvate DH : Regulatory Steps: Links of CAC
the production of ATP Cause lactic acidosis Citrate synthase Gluconeogenesis
the provision of building blocks for Arsenite - Inhibited by: ATP - Lactate enters CAC
biosynthetic reactions Mercury Isocitrate dehydrogenase - Oxidized to pyr then to OAA
to lower blood glucose Deficiency of thiamine - Rate-limiting enzyme - OAA is converted to PEP
- In alcoholics (Alcohol inhibit - Activated by: ADP (phosphoenolpyruvate carboxykinase)
Aerobic glycolysis absorption) - Inhibited by: ATP, NADH Glucogenic AA
Pyruvate : transported to mitochondrion Inherited PDH deficiency -Ketoglutarate dehydrogenase - Propionate via succinyl CoA
Acetyl CoA and enters the CAC - Inhibited by: Succinyl-CoA, ATP, and - PEPCK: Key to transfer to
Products hemolytic anemia: PK def in RBC NADH gluconeogenesis
- ATP fatigue, low exercise capacity: muscle - a-ketoglutarate DH complex favors FA synthesis
- CO2 PFK deficiency succinyl CoA formation - (Cytosol)
- NADH +H - Physiologically unidirectional - Citrate ( CoA) is transported from
- FADH2 PK deficiency - Arsenite ; inhibits mitochondrion
- - Lack of ATP Succinyl CoA synthase: - When aconitase is saturated
Transfer of pyruvate to mitochondrion - Impairs N/K pump - Only substrate level phosphorylation - In cytosol
- Proton/pyruvate symporter - Increase in cell Na - Use of GTP: for decarboxylation of - ATP-citrate lyase cleaves to acetyl
Pyruvate : thru oxidative - Loss of intracellular K and H2O OAA to PEP in gluconeogenesis CoA
decarboxylation will generate acetyl CoA
and CO2 CAC Alternative reaction: Other links of CAC
- Pyruvate dehydrogenase complex final stage for the metabolism of carbo, when ketones are being utlized a-KG and OAA for AA synthesis
- Thiamine pyrophosphate fa, and aa which are oxidized to acetyl (extrahepatic) Succinyl CoA for heme synthesis
- Lipoamide CoA or intermediates Succinyl CoA acetoacetate-CoA Malate for gluconeogenesis
Products oxidative cycle: transferase (thiophorase) transfers CoA
- Acetyl CoA - requires O to acetoacetate: Hemolytic anemia
- NADH - aerobic Acetoacetyl Coa is split to acetyl CoA inherited aldolase A deficiency
- Resp Chain also called Krebs cycle for Hans Krebs (thiolase) for CAC PK deficiency
- CO2 who first described it
Central role in gluconeogenesis, Reactions of CAC Fluoroacetate : inhibits aconitase
Pyruvate DH complex lipogenesis, interconversion of AA Succinate DH (IMM) - Condenses with OAA to form
Pyruvate DH - All processes occur significantly - Contains FAD fluorocitrate
Dihydrolipoyl transacetylase only in liver - Links with ETC (ubiquinone) - Citrate accumulates
Dihydrolipoyl DH Fumarase Arsenite : inhibits a-ketoglutarate DH
- Intermediates remain bound to the CAC cycle : - Adds H2O to form malate - Aketoglutarate accumulates
enzymes; substrates are handed Mito is the power plant of the cell Malate DH Malonate
from one enzyme to the next Engine room : CAC : where the fuels are - Forms OAA +NADH - competitive inhibitor for succinate
fed to be oxidized to CO2 and H2O CAC 1 turn: dehydrogenase
Control of PDH Energy is transferred to electron carriers NADH ; 3 : 9
Inhibited by end product (acetyl CoA and to Oxygen FADH: 1: 2 CAC as amphibolic cycle
and NADH) GTP : 1: 1 Links with CAC
Covalent modification Condensation of OAA and acetyl CO2 : 2
- Kinase phosphorylates (inactive) and OAA is regenerated - ATP : 12 Entry to cycle:
phosphatase removes P (activates) - Only small amt of OAA is needed - 2 turns : 24 Most important: OAA
- Kinase is activated by more ATP, for oxidation of large acetyl Sources
more acetyl CoA (CoA), more NADH - (catalytic role) Role of vit in CAC - Pyruvate carboxylated to OAA
(NAD) therefore inhibit glycolysis Process where free E during oxidation Riboflavin: FAD - Pyruvate carboxylase
- Inhibited when FA are oxidized is made available - Succinate DH Lactate enters CAC
decreased active enzyme carbons lost as CO2 originate from what Niacin : NAD - As OAA (from carboxylation of
- In adipose tissue, enzyme is activated was OAA, not directly from acetyl-CoA - Isocitrate DH, aKG DH, malate DH pyruvate)
in response to insulin, (acetyl CoA is carbons donated by acetyl-CoA become B1: thiamin Dphosphate Glucogenic AA enter CAC
provided by glucose for lipogenesis) part of the oxaloacetate carbon - a-KG DH - Pyruvate (from alanine)
backbone after the first turn of the citric Pantothenic acid - OAA (fr. Aspartate
acid cycle - (part of CoA) - a-kg (from glutamate)
OAA regenerated - succinyl CoA
- Acetyl CoA
CAC role in gluconeogenesis
Intermediates of CAC
Key to transfer of CAC to
gluconeogenesis
PEPCK
GTP (OAA to PEP)
AA may enter gluconeogenesis
Those that form CAC intermediates
Via Pyruvate,a-KG,succinyl
CoA,fumarate
Role of CAC in FA synthesis
Major substrate for FA synthesis : acetyl
CoA
Transport to cytosol: Via citrate
When citrate is in excess due to
saturation of aconitase, the excess
(citrate) is channelled to FA synthesis
Control of CAC
Pyruvate DH
Inhibited by : NADH, acetyl CoA, ATP;
Inhibited when FFA increases
(fasting) (spares CHO)
- Adipose tissue: insulin activates
(acetyl CoA for lipogenesis)
Regulation by Kinase (inactive) and
phosphatase (activate)
- Kinase is activated by ATP, acetyl
CoA, NADH
Important control in Brain tissues
(largely dependent on glucose)
Citrate synthase
Allosteic inhibition by ATP and (long
chain)fatty acyl CoA
Conc of OAA controls citrate
a-Ketogutarate DH
Same as PDH
Isocitrate DH
Allosteric activation by ADP
Succinate DH
Inhibited by OAA, (availability by
malate DH on NADH))
ETC AND OXIDATIVE
PHOSPHORYLATION
Oxidative phosphorylation
the process in which ATP is formed as a
result of the transfer of electrons from
NADH or FADH2 to O2 by electron
carriers
in mitochondria
the major source of ATP in aerobic
organisms
NADH and FADH
- are formed in glycolysis, fatty acid
oxidation, and the citric acid cycle
Electron transport chain
- ATP production
- H2O
energy released by electrons through
ETC is used to transport protons across
IMM in a process called chemiosmosis
The flow of is exergonic process
Components of RC
Complex 1
- NADH - Q oxidoreductase
Complex III
- Q - cytochrome c
Complex IV
- cytochrome c oxidase
Complex II
- Succinate Q reductase
- Succinate Pass to Q
- Conversion of succinate to
fumarate forms succinate Q
reductase (complex II)
- Electrons are passed thru Fe-S to
Q (III)
Fe-S found in I and II; Q accepts from
I(II); NADH passes via FMN then series
of Fe-S then Q (III)
Then to complex III (Q-cytochrome c
oxidoreductase)
Both the electron transport chain and
the ATP synthase are embedded
movements of protons across this
membrane generates potential energy in
the form of H+ (pH gradient and an
electrical potential across this
membrane)
Protons flow back across the membrane
and down this gradient, through ATP
synthase
ATP synthase and F1 complex
in this step, the H+ conc diff bw the
mitochondrial matrix and the
intermembrane space is what provides
the energy to produce ATP
Steps consist of:
- H+ transport: movement of H+
- F1 event: production of ATP
ATP synthase
F1 complex
- Produces ATP
Fo
- Proton channel (spans membrane)
Protons translocated per NADH
- I and II = 4 H
- IV = 2H
ATP formed thru oxidative
phosphorylation
I,III.IV
- Via NADH 2.5/half O2
- P:O ratio of 2.5
Succinate (3-PG)
- Via II, III, IV
- 1.5 ATP
- P:O = 1.5
To acetyl CoA
- 2 NADH (2.5 x 2)/glu = 5 ATP
CAC :
- 6NADH /glu(2.5x6) =15
- 2FADH/glu (1.5x2) = 3
ATP produced per glucose
Control of CAC
Inhibitors of RC
Amobarbital: Block Fe-S to Q (I)
Antimycin Adimercaprol : At III
H2S, CO, cyanide: IV, Arrest RC
Malonate: Competitive inhibitor of II
Atractyloside
- Inhibit transporter of ADP and ATP
out of mitochondrion
Uncouplers
- 2,3 dinitrophenol
- Thermogenin : Found in brown
adipose, to generate heat
- Oligomycin : Block flow of protons
thru ATP synthase
Ionophores
- Facilitate transport of cations thru
membranes
- May be uncouplers
NADH cannot penetrate IMM
Shuttles that carry from cytosol
Glycerophoshate
- Enzyme linked to RC from MM is
FAD, only1.5 ATP/O2 atom
- Brain, white skeletal muscle)
Malate shuttle
- More universal
- NADH + OAA (malate DH) forms
malate (transported to
mitochondrion) then to OAA + NAD
to NADH
- 2.5 ATP
GPDH converts DHAP to 3-G-3-P by
oxidizing NADH to NAD
G-3-P is converted back to DHAP by
membrane-bound mitochondrial G-3-P
oxidase reducing enzyme-bound FAD
toFADH2. then reduces CoQ to ubiquinol
which enters into OP
Is not the exact reversal of glycolysis
Pyruvate may be the starting point
- From glycolysis
- Other sources
3 irreversible steps in glycolysis
- Gluconeogenesis differs from
glycolysis in these points
1. PEP to pyruvate
- the pyruvate kinase
2. fructose -6-phosphate to fructose 1-6-
bisphosphate
- phosphofructokinase-1(PFK-1)
3. G-6-P
- hexokinase/glucokinase catalyzed
reactions
- Gluc to G-6-P
Pyruvate to PEP Glycerol F 2,6-biphosphate Liver
2 steps Propionate Regulates glycolysis and export to maintain blood glucose
1. Pyr to OAA gluconeogenesis between meals
- Pyr carboxylase free glucose can easily diffuse in and Most potent activator of PFK1 Depleted in 12-18 hours of fast
- ATP ,biotin out of the cell Inhibitor of F 1,6-biphosphatase in liver
- Cross IMM as malate or aspartate the phosphorylated form (glucose-6- Formed by phosphorylation of F 6-P by Glycogenesis
2. OAA to PEP (cytosol) phosphate) is locked in the cell PFK-2 Glucose molecules are joined by
- PEP carboxykinase - a mechanism by which intracellular glycogen synthase
- GTP glucose levels are controlled by glucagon, via cAMP stimulates - pre-existing glycogen primer or
F-1,6BP to F-6-P cells. gluconeogenesis and inhibit glycolysis in glycogenin
- F1,6-biphosphatase The final reaction of gluconeogenesis: mammalian liver - (Glycogen initiator synthase)
G-5-P to Glucose the formation of glucose Both insulin and glucagon regulate the
- G-6-phosphatase - occurs in the lumen of the transcription of bypass enzymes Branching enzyme
by pass hexokinase endoplasmic reticulum Amylo (a-1,4 to 1,6) transglycosylase
- G-6-P - glucose-6-phosphatase (produce insulin (glucosyl a- 4:6 transferase)
- G-6-phosphatase glucose) inhibits transcription of
- Liver and kidney, Not in muscle - Glucose is shuttled into the cytosol phosphoenolpyruvate carboxykinase Glycogen: rapidy mobilizable
by glucose transporters located in (PEPCK) (OAA to PEP + CO2) - Skeletal muscles: reserve for ATP
Pyruvate the membrane of the endoplasmic glucagon activates its transcription during muscle contraction
the first designated substrate of the reticulum Increase in ATP (as in hyperglycemia) 1-2% of resting muscle
gluconeogenic pathway, can then be has net effect of Ca influx in pancreatic Liver : maintain blood glucose
used to generate glucose Glycerol: cells causing release of insulin concentration
muscles lack enzyme needed to convert requires phosphorylation to glycerol-3- Enhances glucose transport into adipose 6-8% of well-fed liver
pyruvate to G6P. It must be sent to liver phosphate and muscle, does not affect glucose
- glycerol kinase uptake to liver Synthesis
stoichiometry for gluconeogenesis from dehydrogenation to dihydroxyacetone release Inhibited by epinephrine in Cytosol
pyruvate is: phosphate (DHAP) From a-glucose
2 pyruvate + 4 ATP + 2 GTP + 2 NADH - glyceraldehyde-3-phosphate PEPCK rate limiting of gluconeogenesis UDP-glucose is the source of the
+ 6 H2O glucose + 4 ADP + 2 dehydrogenase (G3PDH) glucosyl residues
GDP + 6 Pi + 2 NAD+ + 2 H+ Glucagon - UDP-glucose phosphorylase
6ATP(GTP) Propionate: Increases gluconeogenesis from amino - glucose 1-P + UTP to produce UDP
2 pyruvate fatty acids with an odd number acid and lactate glucose + UDP + PPi
2 NADH some aa generate propionyl-CoA causes glycogenolysis by stimulating a-D glucose:
converted to the TCA intermediate, phosphorylase in liver - source of glucosyl residues
stoichiometry for conversion of glucose succinyl-CoA has hyperglycemic effect Glucose is phosphorylated to glucose-6-
to pyruvate by glycolysis is: acts thru generation of cAMP phosphate
glucose + 2 ADP + 2 Pi + 2NAD+ 2 Acetyl CoA cannot be used for a glucose polymer that serves as the - ( glucokinase or hexokinase)
pyruvate + 2 ATP + 2 NADH + 2 H2O gluconeogenesis in animals because it bodys quick energy reserve Glucose-6-phosphate is converted into
2pyruvate cannot be converted to oxaloacetate (or chain of glucose molecules linked glucose-1-phosphate
2 ATP other gluconeogenic subtrates). together by alpha(1:4) bonds - (Phosphoglucomutase)
2 NADH plants and some microorganisms can held as a reserve for future energy - G-1,6-BP : intermediate in the
convert acetylCoA into oxaloacetate needs reaction,enzyme is phosphorylated
Von Gierkes disease through the glyoxylate cycle - Rapidly mobilizable form UDP-glucose (active)
Type 1 GSD Major glycogen stores : - readily add to the 4-hydroxyl group
Deficiencies in either glucose-6- PFK 1 rate limiting in glycolysis - the liver (about 100 grams) (6-8%) of a glucosyl residue (4 end of the
phosphatase or any of the three Forms F1,6-BP - in the skeletal muscles (about 400 glycogen chain)
transporters Inhibitors: ATP,PEP, grams) (1-2%) - glycogen synthase
- Accumulation in cell Activators - UDP-glucose is added to the
- symptoms of hypoglycemia - AMP,ADP, Muscle: nonreducing end of glycogen
- F2,6-BP Readily available source for glycolysis molecule
Substrates for Gluconeogenesis within - UDP released is converted to UTP
Lactate PFK 1 No free glucose (nuleoside diphosphate kinase)
Pyruvate (transaminated to Ala) Regulate glycolysis Pyruvate undergoes transamination to
All citric acid cycle intermediates Inhibited by citrate nd ATP alanine exported to liver for
Aa: glucogenic (exc lys or leu ) Activated by AMP gluconeogenesis
 Glucose-1-phosphate + UTP
- converted into UDP-glucose
- (Uridyl Transferase) (also called
UDP-glucose pyrophosphorylase)
Branches are made by branching enzyme
amylo-(1:4) -> (1:6)
transglycosylase)
Glucosyl a-4:6transferase
Transfers a chain from non-reducing
end to another residue by -1:6
glucosidic bond, forming branches,
Degradation :
- Not reversal of synthetic
- Separate set of enzymes
Glycogen degradation consists of
three steps:
1. the release of glucose 1-phosphate from
glycogen
2. the remodeling of the glycogen
substrate to permit further degradation
3. the conversion of glucose 1-phosphate
into glucose 6-phosphate for further
metabolism
Degradation
Cleavage of a-1,4 glycosidic bond at the
non-reducing ends
Glycogen phosphorylase
Pyridoxal phosphate (coenzyme)
G-1-P
Cleavage occurs until 4 glycosyl units
remain before a branch point
Phosphorylase cannot degrade further
Limit dextrin (3)
Removal of branches
2 steps: debranching enzyme (2
activities)
Oligo-(a-1,4 a-1,4)glucantransferase
(Glucosyl (4:4) transferase)
Removes outer 3residues, transfers
them to non-red end of another chain,
exposing the branch
Amylo-a-(1,6) glucosidase: remaining
branch is removed
As free glucose
Conversion of G-1-P to G-6-P
- Phosphoglucomutase
Liver (kidney)
- G-6-phosphatase
Lysosomal enzyme
- a-1,4-glucosidase (acid maltase)
- Continuously degrade small
amount of glycogen
Pompes disease;
glycogen storage disease type II
Deficiency of the enzyme
Accumulation of glycogen in vacuoles in
cytosol
Regulation
Necessary to maintain glucose level
Enzymes are allosterically controlled
- Glycogen synthase
- Glycogen phosphorylase
- Balance between synthase and
phosphorylase regulate glycogen
metab
- Control:
Allosteric mechanism
Covalent modification by
phosphorylation and removl of
same enzyme (by hormone)
Epinephrine, glucagon thru cAMP
(adenyl cyclase)
Hormones
Allosteric regulation
Levels of metabolites and energy needs
in the cell
energy (ATP) and substrate are high :
synthesis
High G-6-P
- activates glycogen synthase
- Inhibits glycogen phosphorylase
(glucose inhibits in the liver)
Energy and available glucose are low :
degradation
Glycogen synthase
Dephosphorylated (synthase a) ; active
Phosphorylated (snthase b) inactive
Kinases
- Ca/calmodulin dependent
(phosphorylase kinase)
- cAMP dep (hormone ) inhibit
synthesis while activating
glycogenolysis
- Insulin mediated inc in G-6-P
stimulates dephosphorylation and
activation of synthase b (protein
phosphatase )
Protein phosphatase Glycogen synthase-P (inactive)
Removes phosphate groups Glycogen synthase (active)
(phosphorylase b) inactive Synthesis
- Insulin : increases synthesis
Phosphorylase kinase Degradation
Phosphorylation to activate - Glucagon (epinephrine)
(phosphorylase a) - Increase degradation
Insulin Control of glucose levels
Thru G-6-P activate protein phosphatase
to activate glycogen synthase a
Well fed
glycogen synthase
- Allostericallyactivated by G-6-P
glycogen phosphorylase
- Allosterically inhibited by G-6-P and
by ATP
Liver
glycogen phosphorylase
- Allosterically inhibited by glucose
Degradation in muscle
Ca, released during muscle contraction
from sarcoplasmic reticulum
- Activates phosphorylase kinase
- By binding to its calmodulin
component
AMP
- Increased In anoxic muscle or ATP
depletion
- Glycogen phosphorylase (b) is
activated when AMP binds
Two hormones which control
glycogenolysis are glucagon from the
pancreas and epinephrine
cAMP
Glucagon ,epinephrine (liver) and
Epinephrine (muscle)
Activates adenylate kinase to produce The pentose phosphate pathway
cAMP primarily an anabolic pathway that
Activates kinase which inactivates utilizes the 6 carbons of glucose to
glycogen synthase generate 5 carbon sugars and reducing
equivalents
Phosphorylase-P a active; degradation
Plase b: inactive Hexose monophosphate shunt
cAMP directed Phosphogluconate pathway
- Glucagon, epinephrine Occurs in the cytosol
- Activates adenylate to form cAMP
Glucose binds to phosphorylase a:
signals degradation to stop
 2 irreversible oxidative reactions
Reversible sugar-phosphate
interconversions
Interconversion reactions can have
different directions
Rate and direction determined by supply
and demand for intermediates
No ATP is directly consumed or
produced
1 CO2 released
- C1 of G-6-P
2 NADPH produced
- Per glucose that enters the
oxidative pathway
Principal products
NADPH
- FA synth (liver and mammary
gland)
- Steroids (adrenal gland)
Ribose P
- For synthesis of nucleotides
- Mechanism for metabolic utilization
of 5-C sugars from diet
Oxidative stage
glucose-6-phosphate (G6P): the
substrate at the beginning of the
pathway and generate NADPH
Transketolase transfers 2 carbon units
(requires thiamine pytophosphate
Transaldolase transfers 3-carbon units
primary functions of this pathway are
1. generate reducing equivalents : NADPH
- For Fatty acid synthesis
2. provide Ribose-5-P for synthesis of
nucleutides
3. metabolize dietary pentose sugar (tho
not significnt function)
The following utilize the NADP+/NADPH
cofactor
- fatty acid biosynthesis and steroid
cells of the liver, adipose tissue,
adrenal cortex, testis and lactating
mammary glands have high levels
of the PPP enzymes
- Reduce glutathione
(gamma-glutamylcysteinylglycine)
erythrocytes
- Glutathione helps prevent oxidative
damage to cells by reducing H2O2
- Transport AA across the
membranes of cells by the gamma-
glutamyl cycle
NADPH
- conversion of ribonucleotides to
deoxyribonucleotides (through the
action of ribonucleotide reductase)
- rapidly proliferating cell needs
large quantities of NADPH
reactions that generate NADPH
glucose-6-phosphate dehydrogenase
6-phosphogluconate dehydrogenase
The non-oxidative reactions
primarily generate ribose 5-phosphate
converts dietary 5 carbon sugars into
both 6 (fructose-6-phosphate) and 3
(glyceraldehyde-3-phosphate) carbon
sugars utilized in glycolysis
Glucose 6-P DH deficiency
Most common enzyme abnormality
X-linked
Increased resistance to falciparum
Impaired ability to form NADPH
unable to detoxify radicals
Alternative sources of NADP for other
tissues:
- NADP dependent malate DH
Oxidant drugs
- Antimalarials, sulfonamides,
acetanilid
Fava beans