Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
next
Basic Sciences Biochemistry Cellular Energy
5 questions
0
The 9 essential amino acids
are histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, t
ryptophan, and valine. These amino acids cannot be synthesized in human cells
and must be obtained from the diet.
less Only L-form (optical isomer) amino acids can be found in proteins.
Mnemonic: Help In Learning These Little Molecules Proves Truly Valuable"
Help = Histidine
In = Isoleucine
Learning = Leucine
These = Threonine
Little = Lysine
Molecules = Methionine
Proves = Phenylalanine
Truly = Tryptophan
Valuable = Valine
The acidic amino acids are aspartic acid and glutamic acid. They are negatively
charged at physiologic pH.
The basic amino acids are arginine, lysine, and histidine. Arginine is the most
basic.Histidine does not have a charge at physiologic pH.
less Found in high concentrations in proteins that need to bind strongly to negative
substrates. For instance, arginine and lysine are over-expressed in histones because
the histones need to bind negatively charged DNA.
Amino acids are divided into glucogenic amino acids and ketogenic amino acids.
Glucogenic amino acids can enter the CAC as either pyruvate, -ketoglutarate,
succinyl-CoA, fumarate, or oxaloacetate and used to produce glucose. The
ketogenic amino acids are degraded to acetyl-CoA or acetoacetate and used to
produce fatty acids or other ketone bodies. These are not mutually exclusive. Some
amino acids are considered both glucogenic and ketogenic.
less The exclusively ketogenic amino acids are leucine and lysine.
The ketogenic and glucogenic amino acids
are threonine, tryptophan, tyrosine,isoleucine, and phenylalanine. Note:
Threonine is converted to glycine and acetyl-CoA via threonine dehydrogenase.
However, some texts do not consider it a ketogenic amino acid.
The exclusively glucogenic amino acids are alanine, arginine, asparagine,
aspartic acid, cysteine, histidine, glutamine, glutamic acid, glycine, serine,
methionine, proline, and valine.
Pyruvate Reactions
next
Basic Sciences Biochemistry Cellular Energy
3 questions
0
Pyruvate can undergo 1 of 4 reactions:
1) Dehydrogenation by the Pyruvate Dehydrogenase Complex to yield acetyl-CoA
less Acetyl CoA enters the Citric Acid Cycle
2) Carboxylation by pyruvate carboxylase to yield oxaloacetate
less Used in Citric Acid Cycle or Gluconeogenesis (frst of 2 steps needed to
convert pyruvate back to PEP)
Requires ATP
3) Transamination by alanine aminotransferase (ALT) to yield alanine
less Tissues (e.g. muscle) that use amino acids for fuel generate glutamate
Glutamate can donate its amino group to pyruvate, yielding alanine
Alanine is transported to the liver, which then regenerates pyruvate and
glutamate
The pyruvate undergoes Gluconeogenesis and is sent out to the body
The glutamate ultimately enters the Urea Cycle urea (nitrogen excretion)
4) Reduction by lactate dehydrogenase to yield lactate
less Consumes NADH
Can enter the Cori cycle
Cori Cycle
next
Basic Sciences Biochemistry Cellular Energy
4 questions
0
During strenuous exercise when oxygen supply is insufcient, muscle cells must
resort to anaerobic metabolism, where pyruvate is reduced by NADH to
form lactate and regenerateNAD
+
, instead of entering the Tricarboxylic Acid (TCA)
Cycle. Lactate dehydrogenase(LDH) is the enzyme responsible for the reaction.
The lactate produced in the muscle cells during anaerobic metabolism enters the
bloodstream and is taken up by the liver. In the liver gluconeogenesis converts
lactate into glucose. Glucose enters the bloodstream and is used by muscle cells,
restarting the cycle.
In the Cori cycle lactate is produced in the muscle cells and converted to glucose in
the liver, so the muscle cells can make more lactate. Glycolysis and anaerobic
metabolism in themuscle cells generate 2 ATP per glucose; gluconeogenesis in
the liver consumes 6 ATPto generate one glucose from two lactate. Overall, 4
net ATP are consumed for each round of the Cori cycle; therefore, there is a
metabolic shift to the liver.
Red blood cells, which lack mitochondria, produce lactate and hence participate in
the Cori cycle.
Pyruvate Dehydrogenase Complex (PDC)
next
Basic Sciences Biochemistry Cellular Energy
4 questions
0
The Pyruvate Dehydrogenase Complex (PDC): converts pyruvate into acetyl-CoA
through several reactions, linking glycolysis (cytoplasm) and the citric acid cycle
(mitochondria)
less PDC is located in the mitochondrial matrix
The transport of pyruvate into mitochondria consumes energy, lowering the
total ATPproduction of aerobic glucose metabolism
The complex has 3 enzymes: E1 (pyruvate dehydrogenase), E2, and E3
Reaction: pyruvate + NAD
+
+ CoA acetyl-CoA + CO
2
+ NADH
E1 requires, as a cofactor, thiamine pyrophosphate (TPP), a derivative of vitamin
B1
less The rate limiting step of the reaction
E2 requires, as cofactors, CoA and lipoic acid
less It is this step that produces acetyl-CoA (hence the need for CoA in this step)
E3 requires, as cofactors, FAD (vitamin B2) and NAD
+
(vitamin B3)
less FAD oxidizes a lipoic acid intermediate back to lipoic acid so it can participate
in more reactions in the process, FAD is reduced to FADH
2
FADH
2
is then used
to reduce NAD+ to NADH
The PDH complex is regulated directly through phosphorylation
less PDH kinase and PDH phosphatase are part of the PDH complex and act on
E1.
Phosphorylation through PDH kinase inhibits E1, while dephosphorylation
through PDHphosphatase activates E1
PDH kinase is activated (which leads to inactivation of E1) by ATP, acetyl-
CoA, andNADH
PDH kinase is inhibited (which leads to activation of E1) by pyruvate
PDC defciency has two typical presentations:
1. Metabolic (lactic acidosis as pyruvate is shunted to lactate)
2. Neurological (hypotonia, poor feeding, lethargy, seizures, mental retardation)
less Most common form is caused by mutations in the X-linked E1 gene
Even though the E1 mutation is X-linked, it still afects females due to critical role of
the enzyme in the nervous system considered X-linked dominant
Key feature: gray matter degeneration with brainstem necrosis and capillary
proliferation
Treatment: very few forms respond to cofactor supplementation with thiamine
Ketogenic diets (high fat, low carbohydrate, adequate protein) have minimal
success
Citric Acid Cycle
next
Basic Sciences Biochemistry Cellular Energy
7 questions
0
Citric Acid Cycle: central catabolic pathway used to generate energy through the
oxidization of acetate (derived from carbohydrates, fats, and proteins) into CO
2
and
H
2
O
For each turn, the cycle produces 1 GTP, 3 NADH, 1 FADH
2
, and 2 CO
2
less 1 NADH 3 ATP equivalents
1 FADH
2
2 ATP equivalents
However, because of the energy expenditure required to shuttle NADH and FADH to
theETC, each turn through the citric acid cycle yields:
3 NADH x 2.5 7.5 ATP equivalent
1 FADH
2
x 1.5 1.5 ATP equivalent
1 GTP 1 ATP equivalent
For a total of 12 potential and 10 actual ATPs
The citric acid cycle (tricarboxylic acid cycle or Krebs cycle) takes place in the
mitochondrial matrix
Citrate synthase catalyzes the transfer of a 2-carbon acetyl group from acetyl-
CoA tooxaloacetate, forming the 6-carbon molecule citrate
less Citrate synthase is inhibited by ATP, NADH and succinyl CoA and stimulated
by insulin
Strongly exergonic step, regulatory point in the cycle
Aconitase catalyzes the isomerization of citrate into isocitrate
less Fluoroacetate (a metabolic poison) inhibits the enzyme aconitase
Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to -
ketoglutarate
less NAD+ NADH, 1
st
molecule of CO
2
is released
Key regulatory step that is stimulated by ADP (low energy state) and inhibited
by ATP andNADH (high energy state)
The -ketoglutarate dehydrogenase complex converts -ketoglutarate to succinyl-
CoA
less NAD+ NADH, 2
nd
molecule of CO
2
is released
Regulatory step, regenerates a 4-carbon chain (CoA excluded) and requires
many coenzymes, including vitamins B1, B2, B3, CoA, and lipoic acid
Note: the same cofactors are required in the pyruvate dehydrogenase complex.
-ketoglutarate dehydrogenase is inhibited by NADH, succinyl
CoA, ATP and GTP
Succinyl-CoA synthetase converts succinyl-CoA to succinate and CoA
less Substrate level phosphorylation: GDP + P
i
GTP
The succinate dehydrogenase complex catalyzes oxidation of succinate to fumarate
less
FAD FADH
2
Mitochondrial fumarase converts fumarate to malate
Malate dehydrogenase oxidizes malate to oxaloacetate, and the cycle can begin
anew
less NAD+ NADH
Electron Transport Chain
next
Basic Sciences Biochemistry Cellular Energy
1 question
0
Electron transport chain: uses NADH and FADH2 electrons (from glycolysis,
pyruvate dehydrogenase complex, and the citric acid cycle) to form a proton gradient,
coupled to oxidative phosphorylation, that drives the production of ATP
less The ETC (electron transport chain) is composed of 5 multi-enzyme
complexes, numbered I-V, that accept and donate electrons while molecular oxygen,
O2, is the fnal electron acceptor
Mobile electron carriers, such as cytochrome c and coenzyme Q, shuttle
electrons between various enzyme complexes of the ETC
Primary NADH electron transport system: malate-aspartate shuttle, which
transportsNADH electrons to complex 1 in the mitochondria.
Less commonly used NADH electron transport system: glycerol-3-phosphate
shuttle
Theoretically: 1 NADH yields 3 ATP and 1 FADH2 yields 2 ATP (because
FADH2 electrons are transferred to complex II, a lower energy level than NADH)
However, since NADH from glycolysis needs to be transported into the mitochondria
and the mitochondrial membrane "leaks" protons, the actual yields are smaller
As electrons fow through the ETC, protons (H+) are pumped into the
mitochondrial inter-membrane space this creates an electrochemical proton
gradient
ATP Synthase (Complex V): uses the electrochemical proton gradient
created by theETC to pump protons (H+) back into the mitochondrial matrix to
produce ATP from ADPand Pi
Toxins that disrupt any component of the ETC disrupt the aerobic production
of ATP tissues that depend highly on aerobic respiration, such as the CNS and
the heart are particularly afected
less Amobarbital (known as amytal) and rotenONE bind to NADH dehydrogenase
(complex 1) directly inhibit electron transport
Antimycin A binds to cytochrome c reductase (complex III) directly inhibits electron
transport
Carbon monoxide and Cyanide bind to Cytochrome C oxidase (complex IV)
directly inhibit electron transport
Oligomycin (a macrolide) inhibits ATP synthase (complex V) by blocking its
proton channel
2,4-Dinitrophenol and doses of aspirin increase the permeability of the
inner mitochondrial membrane proton gradient and oxygen consumption
heat generated instead of ATP (explains the fever generated following toxic doses of
aspirin)
Thermogenin in brown fat is an uncoupling agent that disrupts the proton
gradient used to generate heat in animals
HMP hunt (Pentose phosphate path!ay)
next
Basic Sciences Biochemistry Cellular Energy
4 questions
0
HMP Shunt: a 2 phase pathway consisting of an oxidative (irreversible) phase
andnonoxidative (reversible) phase that uses available glucose-6-phosphate to
mainly produce NADPH and ribose-5-phosphate
less Both phases occur in cytosol
ATP is not used or produced!
Key reactions:
1) Glucose-6-Phospate Ribulose-5-Phospate + 2 NADPH
*Enzyme: Glucose-6-Phosphate Dehydrogenase
2) Ribulose-5-Phosphate Ribose-5-Phosphate + G3P + F6P
*Enzyme: Transketolase
Oxidative phase: key enzyme is G6P dehydrogenase (G6PD), the rate-limiting
enzyme; all steps of the oxidative phase are irreversible and are used to
generate NADPH for reductive biosynthetic pathways
less NADPH is used to reduce glutathione, a coenzyme for glutathione
peroxidase which prevents oxidative damage by converting H
2
O
2
H
2
O. This is
especially important in RBCs
Increased in tissues that consume NADPH in reductive pathways like adipose
tissue for fatty acid synthesis, gonads and adrenal cortex for steroid synthesis, liver
for fatty acid and cholesterol synthesis, and glutathione reduction inside RBCs
Nonoxidative phase: key enzyme is transketolase (thiamine-dependent); all
steps arereversible and are used to convert sugars to produce ribose-5-phosphate
and intermediates for glycolysis and gluconeogensis
less Pentose sugars like ribose-5-phosphate are used for nucleotide synthesis
Fructose-6-phosphate and glyceraldehyde 3-phosphate (products of the non-
oxidative phase) are used as substrates for glycolysis in fed state, and intermediates
in gluconeogenesis in the fasting state
G6PD defciency: hemolytic anemia when RBCs are exposed to oxidative stress
because of inadequate NADPH production leading to less anti-oxidant activity of
glutathione
less Causes of oxidizing stress: infections, fava beans, drugs (e.g. sulfonamides,
dapsone, primaquine)
Transmitted in X-linked recessive fashion with a predominance in Asia, the
Mediterranean, and Africa (disease provides protection against Plasmodium
falciparum malaria)
On a peripheral smear look for Heinz bodies (inclusions in RBCs composed
of denaturedHemoglobin) and degmacytes (bite cells) (result of splenic
macrophages removing Heinz bodies)
Mono"Disaccharide Meta#olic Disorders
next
Basic Sciences Biochemistry Cellular Energy
4 questions
0
Hereditary fructose intolerance: autosomal recessive defciency of aldolase B,
which cleaves fructose 1-phosphate to 3-carbon molecules.
less A defciency in aldolase B leads to accumulation of phosphorylated fructose
available phosphate levels drop gluconeogenesis is blocked
Symptoms: hypoglycemia, vomiting, jaundice, and cirrhosis
Patients usually asymptomatic until challenged, in infancy, with fructose
Treatment: avoid intake of fructose or sucrose (combination of glucose and
fructose)
Essential fructosuria: autosomal recessive, benign condition resulting from defect
in hepatic fructokinase
less Fructose can not be phosphorylated, so it is unable to be sequestered in the
cell elevated serum fructose levels fructosuria
Classic galactosemia: autosomal recessive defciency in GALT (galactose-1-
phosphate uridyl transferase), which converts galactose-1-phosphate to glucose-1-
phosphate
less Absence of GALT leads to galactose-1-phosphate accumulation toxic
All states mandate neonatal screening because lactose (i.e. milk) is
metabolized to glucose and galactose
Symptoms: poor growth, hepatic dysfunction (jaundice, coagulopathy,
hepatomegaly), ascites, cataracts, mental retardation
These infants also have an risk for E. coli septicemia.
Treatment: galactose-free diet
Galactokinase defciency: autosomal recessive defciency in galactokinase, which
phosphorylates galactose to make galactose-1-phosphate
less Accumulation of galactose galactosemia galactosuria
Galactosemia cataracts because the lens of the eye contains aldose
reductase, which converts galactose to galactitol, an osmotically active alcohol
Lactase defciency: age-related or hereditary lactose intolerance due to
expression of lactase (a brush-border enzyme) or transient expression following
gastroenteritis
less Symptoms: osmotic diarrhea, bloating/cramps
Treatment: avoid lactose
Sorbitol accumulation: high blood levels of glucose (or fructose or galactose) lead
to osmotic damage from sorbitol accumulation in tissues that lack sorbitol
dehydrogenase cataracts, diabetic retinopathy, and peripheral neuropathy
less Liver, ovaries, and seminal vesicles have both aldose reductase and sorbitol
dehydrogenase (thus, there is no sorbitol accumulation)
Glucose sorbitol (via aldose reductase) fructose via (sorbitol
dehydrogenase)
Schwann cells, lens, retina, and kidneys only have aldose reductase (thus,
there is sorbitol accumulation in hyperglycemic states)
Phenylalanine $ Tyrosine Meta#olism
next
Basic Sciences Biochemistry Cellular Energy
6 questions
0
Phenylalanine hydroxylase (PAH): enzyme that converts Phenylalanine to Tyrosine
less In this reaction, tetrahydrobiopterin (BH
4
), the required cofactor, is converted
to dihydrobiopterin (BH
2
)
BH
2
is converted back to BH
4
via the enzyme dihydrobiopterin reductase
Tyrosine is a precursor for many catecholamines, neurotransmitters, melanin
and thyroid hormones
Phenylketonuria (PKU): autosomal recessive defects in the enzyme phenylalanine
hydroxylase (PAH)
less Phenylalanine accumulates and leads to the following symptoms:
- neurologic defects (e.g. seizures and mental retardation)
- albinism (tyrosine required for melanin synthesis)
- "musty odor" to their sweat & urine (due to accumulated phenylalanine conversion
to phenylketones)
Screened for on the 2
nd
or 3
rd
day of life due to presence of maternal enzyme
at birth
Treatment: restrict phenylalanine and aspartame (contains phenylalanine) in
diet and tyrosine intake (becomes an essential amino acid)
Maternal PKU: lack of proper dietary treatment in a pregnant woman with PKU
infant born with microcephaly, congenital heart defects, mental and growth
retardation
Malignant PKU: autosomal recessive defects in the enzyme dihydrobiopterin
reductase (called malignant because restricting phenylalanine does not correct
neurological problems)
Note: in malignant PKU, BH
2
is not converted back to BH
4
because of a defect in
dihydrobiopterin reductase so DOPA needs to be supplemented in these patients
Tyrosine hydroxylase: enzyme that converts Tyrosine to Di-hydrOxy-PhenylAlanine
(orDOPA)
less (BH4) is a necessary co-factor for the enzyme tyrosine hydroxylase. (BH4) is
also a co-factor for phenylalanine hydroxylase.
Tyrosinase: similar to tyrosine hydroxylase in that it converts Tyrosine to DOPA, but
this enzyme has further catalytic activity that results in the production of melanin
from DOPA
less Autosomal recessive defects in tyrosinase or albinism: absence of melanin
in hair (white hair), eyes (photophobia), and skin (increased risk of UV related skin
cancer
Homogentisic acid dioxygenase (HGD): enzyme that is part of the degradative
pathway of tyrosine into fumarate
less The catabolic process involves homogentisate (or alkapton) as an
intermediate
Congenital defciency of HGD (or alkaptonuria), autosomal recessive
disease with the following symptoms:
- homogentisate excreted in urine (if the urine is left standing it will turn black)
- homogentisate also polymerizes and deposits in joints joint arthritis, ankylosis,
and arthralgias (toxic to cartilage)
- dark connective tissue (called ochronosis)
- brown hyper-pigmented sclera
%ranched&chain 'etoaciduria (Maple yrup
(rine Disease)
next
Basic Sciences Biochemistry Cellular Energy
1 question
0
Branched chain ketoaciduria (maple syrup urine disease): autosomal
recessive defect in the branched-chain -ketoacid dehydrogenase complex (BCKD)
less The BCKD complex catalyzes the breakdown of Isoleucine, Leucine,
and Valine
Mnemonic: I Love Vermont maple syrup from trees with branches
Defective BCKD accumulation of branched chain amino acids in the blood
and the brain irreversible neurological damage
Symptoms typically present in the frst few days of life (days 4-7) and include
poor feeding, vomiting, poor weight gain, lethargy, and maple syrup odor to the urine
Isoleucine: characteristic maple syrup odor of the urine
Leucine: readily crosses the blood-brain barrier and is responsible for the
neurological symptoms
Treatment: restrict amino acid intake, and a small number of patients respond
to thiamine (vitamin B
1
) supplementation
)ipoprotein Complexes and
Apolipoproteins
next
Basic Sciences Biochemistry Cellular Energy
1 question
0
Lipoprotein complexes are composed of cholesterol, TGs (triglycerides), and
phospholipids and apolipoproteins.
less Lipoprotein complexes include: chylomicrons, VLDL, IDL, LDL, and HDL
Apolipoproteins are proteins that bind to lipids; they have various functions:
less ApoA-I activates LCAT
ApoB-100 is the sole protein component of LDL
ApoB-48 lacks the LDL-receptor binding sequence that ApoB-100 has. It is a
component of chylomicrons.
ApoC-II activates lipoprotein lipase (LPL) in capillaries
ApoE mediates chylomicron and IDL uptake in the liver.
*lucose Transport
next
Basic Sciences Biochemistry Cellular Energy
5 questions
0
All GLUT transporters work via facilitated difusion
GLUT1: most cell types including RBCs and brain
GLUT2 (bidirectional): pancreatic islet cells, liver, renal tubular cells, small intestine
less Low afnity and high capacity isoform liver needs to be
glycogen/glucose reservoir, but shouldnt compete with other tissues
This should look similar to glucokinase (low afnity or K
m
and high capacity or
V
max
) because it has a similar tissue distribution
GLUT3: neurons, testes, and the placenta
GLUT4: adipose tissue and striated muscle (skeletal and cardiac)
less Insulin regulates insertion of GLUT4 transporters into cell membrane in
response to high glucose levels
'etones
next
Basic Sciences Biochemistry Cellular Energy
3 questions
0
Acetoacetate, -hydroxybutyrate, and acetone are the ketones produced during
ketogenesis: Produced by liver for use in the brain and heart.
less Most other tissues can use fatty acids, but brain cannot. The liver lacks the
enzymes to use ketones
During hypoglycemia, fatty acids are sent to the liver for oxidation acetyl-CoA
levels.
less The rate limiting enzyme in the formation of ketones is HMG-CoA synthase.
Ketone utilization: If the ketone is acetoacetate, this is converted (via multiple steps)
to 2 acetyl-CoA molecules that enter the TCA cycle
less If the ketone is -hydroxybutyrate, it is converted back to acetoacetate, then
2 acetyl-CoA
Ketones are excreted in urine. Acetone, from spontaneous decarboxylation of
acetoacetate, causes the "fruity odor" detected on breath during ketoacidosis
Diabetic ketoacidosis: insulin (mostly in Type I diabetes) leads to ketone
production because cells are unable to utilize serum glucose without insulin (
glucose in cells oxaloacetate is shunted into gluconeogenesis stops
the TCA cycle acetyl CoA is shunted into ketogenesis)
Methylmalonic and Propionic Acidemia
next
Basic Sciences Biochemistry Cellular Energy
3 questions
0
Methylmalonic acidemia and Propionic acidemia: autosomal recessive disorders
of enzymes in the pathway that converts propionyl CoA to succinyl CoA (process that
produces energy or glucose from odd-chain fatty acids or certain amino acids)
less Pathway: propionyl CoA methylmalonyl CoA succinyl CoA
Propionyl CoA carboxylase: enzyme that catalyzes the conversion of
proprionyl CoA to methylmalonyl CoA (defciency of this enzyme leads to propionic
acidemia)
Methylmalonyl CoA mutase: enzyme that catalyzes the conversion of
methylmalonyl CoA to succinyl CoA, requiring vitamin B12 as a cofactor (defciency
of this enzyme leads to methylmalonic acidemia)
Symptoms of both include: ketosis, metabolic acidosis, vomiting, lethargy,
poor feeding, neutropenia, and developmental/neurological complications
Propionic acidemia levels of propionic acid in the blood
Methylmalonic acidemia levels of propionic acid and levels of methylmalonic
acid in the blood
Need to rule out vitamin B
12
defciency with methylmalonic acidemia because
some neurologic symptoms are reversible
Treatment for both: low-protein diet (specifcally intake of methionine, valine,
threonine, isoleucine, and odd-chain fatty acids because they are all broken down
into propionyl CoA) and carnitine supplementation (improves -oxidation of fatty
acids)
Hemoglo#in (H#)
next
Basic Sciences Biochemistry Cellular Energy
6 questions
0
Tetramer (4 subunits); each subunit polypeptide has a heme molecule at its center
and each heme molecule can carry 1 oxygen molecule
less
Hemoglobin A (adult):
2
Hemoglobin A2 (adult):
2
Hemoglobin F (fetal):
2
2
elevated in sickle-cell disease patients
Hemoglobins oxygen dissociation curve is sigmoidal: the tetramer fips between 2
conformations
less Deoxy or T (Taut) form: low O
2
afnity
Oxy or R (Relaxed) form: high ( 300x) O
2
afnity
When 2 O
2
molecules are bound to the T form, conformation switches to R
and all 4 sites can be flled
The T to R shift occurs under conditions of high oxygen tension (i.e. the
lungs) and the R to T shift occurs under conditions of low oxygen tension.
Lung: High O
2
oxygenated Hb.
Tissues: Low O
2
deoxygenated Hb (Bohr efect: CO
2
and/or H
+
concentration
stabilizes deoxygenated conformation).
4 factors cause O
2
dissociation (T form favored):
less 1) pH: relative acidic environment, like peripheral tissues
2) CO
2
: produced by cellular metabolism
3) 2,3-DPG (diphosphoglycerate, the same as bisphosphoglycerate):
stabilizes the T conformation, produced by glycolysis
4) temperature
These factors shift the O
2
dissociation curve to the right a higher
O
2
pressure is needed to maintain the same level of hemoglobin saturation
Myoglobin has a similar structure/sequence, but is a monomer doesnt exhibit
cooperative binding
CO
2
transport: CO
2
is converted to H
2
CO
3
by carbonic anhydrase
less
H
2
CO
3
(carbonic acid) dissociates to bicarbonate and a proton; the H
+
binds to
hemoglobin and thus has no efect on serum pH
Allosteric inhibition: CO
2
also binds at the hemoglobin chain N terminus,
favoring the deoxy Hb form
Carbon monoxide: CO is a competitive inhibitor with 200x afnity for heme
compared to O
2
less Carboxyhemoglobin is bright red and poisoned patients are commonly
described as having a cherry-red appearance to their skin
Iron in Hb is usually in the Fe
2+
(ferrous), reduced state
less Methemoglobinemia: oxidation to the Fe
3+
(ferric) state leads to decreased
afnity of O
2
at these heme sites; however, at other non-oxidized heme sites, there is
a compensatory increase in afnity leading to a left shift of the oxygen-
dissociation curve
Normally, oxidation is prevented via a reductive enzyme pathway (HMP shunt)
in RBCs
Drugs that cause
methemoglobinemia: Metoclopramide, Procaine, Nitrites, Antimalarials,Sulfonamides
, Dapsone.
Can be easily remembered with mnemonic: A Methemoglobinemic Patient
is Not AlwaysSomething Deadly.
Treatment: methylene blue
Cyanide poisoning: CN
-
preferentially binds to Fe
3+
and inactivates cytochrome c
oxidasein the electron transport chain stops cellular respiration
less Nitrites can be used to convert Hb to methemoglobin methemoglobin then
binds the CN
-
use sodium thiosulfate to chelate this CN
-
and yield thiocyanate
renally excreted
Methemoglobinemia decreases the patients O
2
carrying capacity, but
methemoglobinemia can be managed whereas arrested cellular respiration is
irreversible
AM (&Adenosyl Methionine)
next
Basic Sciences Biochemistry Cellular Energy
1 question
0
SAM (S-Adenosyl Methionine): the primary methyl donor of the body
less Helps methylate DNA
After donating its methyl group, SAM is hydrolyzed to homocysteine and
adenosine; regeneration of methionine from homocysteine requires folate and
vitamin B12
+atty Acid ,xidation
next
Basic Sciences Biochemistry Cellular Energy
5 questions
0
In the cytosol, long chain (> 14 C) free fatty acids are converted to fatty acyl-CoA
by fatty acyl CoA synthetase. This step activates the fatty acid for transport into the
mitochondria.
Because the inner mitochondrial membrane is impermeable to CoA, the carnitine
shuttle system is required to transport the fatty acyl CoA into the mitochondrial
matrix.
less Step 1:
Enzyme: CAT-I (carnitine acyl transferase I) on the outer mitochondrial membrane
Reaction: Fatty acyl-CoA + carnitine fatty acyl carnitine + free CoA
CoA remains in the cytosol, and fatty acyl carnitine can now pass through the inner
mitochondrial membrane.
Step 2:
Enzyme: CAT-II on the inner surface of the inner mitochondrial membrane
Reaction: Fatty acyl carnitine + CoA (already in the mitochondrial matrix) fatty acyl
CoA + free carnitine
Fatty acyl CoA stays in the mitochondrial matrix for further metabolism, and carnitine
leaves the matrix to be used again in the shuttle.
Carnitine defciency decreased ability to utilize long chain fatty acids as a
fuel source. Can be due to environmental (e.g. malnutrition) or genetic factors
(e.g. CAT-I defciency).
Symptoms: Muscle aches and fatigue following exercise, free fatty acid levels in
the blood, hypoketotic hypoglycemia.
Treatment: Diet high in carbohydrates and medium and short chain fatty acids, low
in long chain fatty acids.
Malonyl-CoA, an intermediate in fatty acid biosynthesis, inhibits this shuttle
system to prevent newly synthesized fatty acids from entering the degradation
pathway, and thus prevent a futile synthesis-degradation cycle
Medium and short chain fatty acids directly enter the mitochondrial matrix without
need for a special transport.
less In the mitochondrial matrix, fatty acyl-CoA synthetase activates short/medium
chain fatty acids to fatty acyl-CoA molecules.
MCADD (medium-chain acyl-CoA dehydrogenase defciency): MCAD is a
enzyme required for complete oxidation of medium length fatty acids. Defciency
inability to oxidize fatty acids with <12 carbons.
Presents with symptoms of hypoglycemia.
Treatment: Avoid prolonged fasting, carbohydrate and protein intake, fat intake.
Inside the mitochondria, fatty acyl-CoA with an even number of carbons undergo
successive rounds of oxidation, yielding acetyl-CoA, and NADH & FADH
2
.
less Acetyl-CoA enters the citric acid cycle.
NADH and FADH~2~ are used in the electron transport chain.
Oxidation of fatty acids containing an odd number of carbons Acetyl-
CoA and Propionyl-CoA
less Because Propionyl-CoA Succinyl-CoA, it is the only part of fatty acids that
isgluconeogenic.
Ketogenesis occurs when there is a high rate of fatty acid oxidation forming Acetyl-
CoA
less When the liver is overloaded with Acetyl-CoA ketone bodies form
The 2 main ketone bodies are acetoacetate and -hydroxybutyrate
Acetoacetate undergoes spontaneous decarboxylation to form acetone
Ketones are generally used in 2 ways:
1) Extrahepatic tissues can convert ketone bodies Acetyl-CoA
2) Because ketone bodies are volatile, they are readily exhaled by the lungs (Note:
This is why diabetics in DKA have fruity smelling breath)
Regulation o- *lycolysis
next
Basic Sciences Biochemistry Cellular Energy
5 questions
0
Regulation points indicate places where intermediates can be shunted in and out of
glycolysis. Examples:
1. Shunting into glycolysis: Glycogenolysis produces G6P that enters the glycolytic
pathway after the 1st regulated reaction.
2. Shunting out of glycolysis: DHAP can be turned into glycerol-3-phosphate
instead ofGADP. Glycerol-3-phosphate is then shunted into triglycerides synthesis.
There are 3 key regulated glycolytic enzymes: Hexokinase/glucokinase, PFK-1 and
pyruvate kinase
Hexokinase: Inhibited by G6P and not induced by insulin
Glucokinase: Not inhibited by G6P but is induced by insulin
Remember glucokinase is induced by insulin.
less