Pyruvate is oxidatively decarboxylated by pyruvate dehydrogenase (PDH) complex, producing acetyl coenzyme A (CoA), which is the major fuel for the tricarboxylic acid cycle.
CHAPTER SUMMARY
Pyruvate is oxidatively
decarboxylated by pyruvate dehydrogenase (PDH) complex, producing acetyl
coenzyme A (CoA), which is the major fuel for the tricarboxylic acid cycle
([TCA cycle] Figure 9.9). This multienzyme complex requires five coenzymes:
thiamine pyrophosphate, lipoic acid, flavin adenine dinucleotide (FAD),
nicotinamide adenine dinucleotide (NAD+), and CoA. PDH complex is
regulated by covalent modification of E1 (pyruvate decarboxylase) b y PDH
kinase and PDH phosphatase: phosphorylation inhibits E1. PDH kinase is
allosterically activated by ATP, acetyl CoA, and NADH and inhibited by
pyruvate. The phosphatase is activated by Ca2+. PDH complex
deficiency is the most common biochemical cause of congenital lactic acidosis.
The central nervous system is particularly affected in this X-linked dominant
disorder. Arsenic poisoning causes inactivation of the PDH complex by binding
to lipoic acid. Citrate is synthesized from oxaloacetate and acetyl CoA by
citrate synthase. This enzyme is subject to product inhibition by citrate. Citrate
is isomerized to isocitrate by aconitase (aconitate hydratase) . Isocitrate is
oxidatively decarboxylated by isocitrate dehydrogenase to α-ketoglutarate,
producing CO2 and NADH. The enzyme is inhibited by ATP and NADH, and
activated by ADP and Ca2+. α-Ketoglutarate is oxidatively
decarboxylated to succinyl CoA by the α-ketoglutarate dehydrogenase complex,
producing CO2 and NADH. The enzyme is very similar to the PDH
complex and uses the same coenzymes. α-Ketoglutarate dehydrogenase complex is
activated by Ca+2 and inhibited by NADH and succinyl CoA but is not
covalently regulated. Succinyl CoA is cleaved by succinate thiokinase (also
called succinyl CoA synthetase), producing succinate and GTP. This is an
example of substrate-level phosphorylation. Succinate is oxidized to fumarate
by succinate dehydrogenase, producing FADH2.
Fumarate is hydrated to
malate by fumarase (fumarate hydratase), and malate is oxidized to oxaloacetate
by malate dehydrogenase, producing NADH. Three NADH, one FADH2, and
one GTP (whose terminal phosphate can be transferred to ADP by nucleoside
diphosphate kinase, producing ATP) are produced by one round of the TCA cycle.
The generation of acetyl CoA by the oxidation of pyruvate via the PDH complex
also produces an NADH. Oxidation of the NADH and FADH2 by the
electron transport chain yields 14 ATP. An additional ATP (GTP) comes from
substrate level phosphorylation in the TCA cycle. Therefore, a total of 15 ATP
are produced from the complete mitochondrial oxidation of pyruvate to CO2.
Figure 9.9 Key concept map
for the tricarboxylic acid (TCA) cycle. CoA = coenzyme A; NAD(H) = nicotinamide
adenine dinucleotide; FAD(H2) = flavin adenine dinucleotide; GDP =
guanosine diphosphate; GTP = guanosine triphosphate; ADP = adenosine diphosphate; Pi = inorganic
phosphate.
9.1 The conversion of pyruvate to acetyl coenzyme A
and CO2:
A. involves the participation of lipoic acid.
B. is activated when
pyruvate decarboxylase of the pyruvate dehydrogenase (PDH) complex is
phosphorylated by PDH kinase in the presence of ATP.
C. is reversible.
D. occurs in the
cytosol.
E. requires the
coenzyme biotin.
Correct answer = A. Lipoic acid is an intermediate
acceptor of the acetyl group formed in the reaction. Pyruvate dehydrogenase
complex catalyzes an irreversible reaction that is inhibited when the
decarboxylase component is phosphorylated. The enzyme complex is located in the
mitochondrial matrix. Biotin is utilized by carboxylases, not decarboxylases.
9.2 Which one of the following conditions decreases
the oxidation of acetyl coenzyme A by the citric acid cycle?
A. A high availability
of calcium
B. A high acetyl
CoA/CoA ratio
C. A low ATP/ADP ratio
D. A low NAD+/NADH ratio
Correct answer = D. A low NAD+/NADH ratio
limits the rates of the NAD+-requiring dehydrogenases. High
availability of calcium and substrate (acetyl CoA), and a low ATP/ADP ratio
stimulates the cycle.
9.3 The following is the sum of three steps in the
citric acid cycle.
A+B+FAD+H2O →
C+FADH2+NADH
Choose the lettered
answer that corresponds to the missing “A,” “B,” and “C” in the equation.
Correct answer = B.
Succinate + NAD+ + FAD + H2O → oxaloacetate + NADH + FADH2
9.4 A 1-month-old male shows neurologic problems
and lactic acidosis. Enzyme assay for pyruvate dehydrogenase (PDH) complex
activity on extracts of cultured skin fibroblasts showed 5% of normal activity
with a low concentration of thiamine pyrophosphate (TPP), but 80% of normal activity
when the assay contained a thousand-fold higher concentration of TPP. Which one
of the following statements concerning this patient is correct?
A. Administration of thiamine is expected to reduce
his serum lactate level and improve his clinical symptoms.
B. A high carbohydrate
diet would be expected to be beneficial for this patient.
C. Citrate production
from aerobic glycolysis is expected to be increased.
D. PDH kinase, a
regulatory enzyme of the PDH complex, is expected to be active.
Correct answer = A. The patient appears to have a
thiamine-responsive pyruvate dehydrogenase (PDH) complex deficiency. The
pyruvate decarboxylase (E1) component of the PDH complex fails to bind thiamine
pyrophosphate at low concentration, but shows significant activity at a high
concentration of the coenzyme. This mutation, which affects the Km of the
enzyme for the coenzyme, is present in some, but not all, cases of PDH complex
deficiency. Because the PDH complex is an integral part of carbohydrate
metabolism, a diet low in carbohydrates would be expected to blunt the effects
of the enzyme deficiency. Aerobic glycolysis generates pyruvate, the substrate
of the PDH complex. Decreased activity of the complex decreases production of
acetyl coenzyme A, a substrate for citrate synthase. PDH kinase is
allosterically inhibited by pyruvate and, therefore, is inactive.
9.5 Which coenzyme-cosubstrate is used by the
dehydrogenases of both glycolysis and the tricarboxylic acid cycle?
Oxidized nicotinamide
adenine dinucleotide (NAD+) is used by glyceraldehyde 3-phosphate
dehydrogenase of glycolysis and by isocitrate dehydrogenase, α-ketoglutarate
dehydrogenase, and malate dehydrogenase of the tricarboxylic acid cycle.
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