Lec 4 Kerbs - Cycle

Lec.
4
Krebs Cycle
Ehab Abdel-Raouf
Depending on the presence of oxygen, the pyruvate will either enter a
fermentation process (lactic acid or alcohol) or proceed towards the Krebs
Cycle.
cytosol Mitochodria
first second third

stage stag
G Pyr Py
stage
r CH3CO~SCoA e
glycolyti TAC CO2 + H2O+ATP
c
pathway
Sir Hans Adolf Krebs
A German-born British physician and
biochemis] He was the pioneer scientist in
study of cellular respiration, a biochemical
pathway in cells for production of energy. He is
best known for his discoveries of two
important chemical reactions in the body,
namely the urea cycle and the citric acid cycle.
The latter, the key sequence of metabolic
reactions that produces energy in cells, often
eponymously known as the "Krebs cycle",
earned him a Nobel Prize in Physiology or
Medicine in 1953
 The tricarboxylic acid cycle (TCA cycle, also called the
Krebs cycle or the citric acid cycle) plays several roles in
metabolism.
 It is the final pathway where the oxidative metabolism of

carbohydrates, amino acids, and fatty acids converge, their
carbon skeletons being converted to CO2.
 This oxidation provides energy for the production of the

majority
of ATP in most animals, including
humans.
 The cycle occurs totally in the

mitochondria.
 The TCA cycle is an aerobic

pathway.
 The citric acid cycle also supplies intermediates for a
of important synthetic reactions. For example,
number
thecycle functions in the glucose from the

formation of carbon skeletons of
some amino acids,
it provides building blocks for the synthesis of some
amino
acids.
Therefore, this cycle should not be viewed as a closed circle,

but instead as a traffic circle with compounds entering and
leaving as required.
II. REACTIONS OF
THE TCA CYCLE
A. Oxidative decarboxylation
of pyruvate
Pyruvate, the end product of aerobic glycolysis, must be

transported into the mitochondrion before it can enter the TCA cycle.
 This is accomplished by a specific pyruvate transporter that

helps
pyruvate cross the inner mitochondrial
membrane.
Once in the matrix, pyruvate is converted to acetyl CoA by

the pyruvate dehydrogenase complex, which is a
multienzyme complex.
irreversible;
in mitochodria.
Pyruvate Oxidation
- transition step between glycolysis and
Kreb's Cycle
CoA-
SH
2) Tricarboxylic acid cycle,
TCAC
 The cycle comprises the combination of
a molecule of acetyl-CoA with

oxaloacetate, resulting in the formation of
a six-carbon tricarboxylic acid, citrate.
There follows a series of reactions in the
course of which two molecules of CO2 are
released and oxaloacetate is regenerated.
 Also called citrate cycle or Krebs cycle.
(1) Process of reactions
CH3CO~SCoA
HSCoA CH2 COO H2O CH2 COO
acetyl CoA
CO COO HO C COO C COO
CH2 COO citrate aconitase
H O synthase CH COO
oxaloacetate 2 CH2 COO
citrate cis-aconitate
NADH+H+
malate dehydrogenase H2O
NAD+ aconitase
HO CH COO
malate CH2
CH2 COO
Citrate cycle isocitrate COO CH
fumarase
H2O HO COO
CH COO
HC COO NAD+
fumarate
OOC CH isocitrate dehydrogenase
+ CO2
FADH2succinate dehydrogenase NADH+H
FAD succinyl CoA CH2 COO NADH+H+ NAD+ CH2 COO

CH2 COO
syntetase
CH2 CH2
CH2 COO GDP+Pi CO~ SCoA CO2 HSCoA COCOO
CoASH GTP
succinate succinyl-CoA ¦Á-ketoglutarate ¦Á-keto-
ADP ATP
dehydrogenase glutarate
complex
① Summary of Krebs Cycle
Reducing
equivalent
s
② The net reaction of the TCAC:
acetylCoA+3NAD++FAD+GDP+Pi+2H2O
→ 2CO2+3NADH+3H++FADH2+GTP+
HSCoA
① Acts as the final common pathway for
the oxidation of carbohydrates, lipids,
and proteins.
② Serves as the crossroad for the

interconversion among carbohydrates,
lipids, and non-essential amino acids,
and as a source of biosynthetic
intermediates.
Figure 9.8. Number of ATP molecules produced from
the oxidation of one molecule of acetyl CoA (using both
substrate-level and oxidative phosphorylation).
2. ATP produced in the
aerobic oxidation
 acetyl CoA → TCAC : 3
(NADH+H+) + FADH2 + 1GTP → 12
ATP.
 pyruvate →acetyl CoA: NADH+H+ →
3 ATP
1 G → 2 pyruvate : 2(NADH+H+) →
1mol
8ATP 38 mol
G： ATP
（ 12 ＋ 3 ） ×2 ＋（ 8 ）＝（
38 ）
Bioenergetics of Glucose
• The metabolism of glucose is representative of that of

carbohydrates. If we begin with 1 mole of glucose (180
g) and oxidize it with 6 moles of oxygen molecules,
there are 6 moles of carbon dioxide, 6 moles of water
and 686 kcal of energy produced. The energy produced
per mass of fuel is 686 kcal/180 g glucose = 3.80 kcal/g
glucose.
Regulation of
Kreb’s Cycle
Pyruvate Dehydrogenase Complex
 A. Regulation by activation and inhibition

of enzyme activity:
Citrate synthase
Isocitrate dehydrogenase (rate-limiting )
-Ketoglutarate dehydrogenase
Regulation of pyruvate dehydrogenase complex
 Allosteric activator: ADP
(2) Citrate synthase
Allosteric inhibitor: NADH, succinyl
CoA,
citrate, ATP
(3) Isocitrate dehydrogenase

 Allosteric activator: ADP, Ca2+
 Allosteric inhibitor: ATP
(4) -Ketoglutarate dehydrogenase

 Similar with Pyruvate dehydrogenase
complex
Inhibitors and activators of the cycle.
B. Regulation by availability of ADP
1. Effect of elevated ADP:
 Energy consumption as a result of

muscular contraction, biosynthetic reactions
or other processes result in hydrolysis
of ATP to ADP & Pi.
 Resulting increase in conc of ADP

accelerates rate of reactions that use ADP to
generate ATP.
2. Effect of low ADP:
 If ADP (or Pi) is present in limiting conc,

formation of ATP decreases.
 Oxidation of NADH & FADH2 by ETC

also stops if ADP is limiting. This is because
the processes of oxidation & phospho are
tightly coupled & occur simultaneously.
 As NADH & FADH2 accumulate, their

oxidized forms become depleted causing
oxidation of acetyl CoA by the TCA cycle to
be inhibited as a result of a lack of oxidized
coenzymes.
Figure 9.3
Mechanism of action of the pyruvate dehydrogenase complex. TPP
= thiamine pyrophosphate; L = lipoic acid.
Pyruvate dehydrogenase complex:
HSCoA
NAD+
Thiamine – Niacin- liopoic acid
Pyruvate dehydrogenase complex:
thiamine pyrophosphate, TPP

HSCoA
cofactors lipoic
Acid NAD+
FAD
• Deficiencies of thiamine or niacin can cause serious central nervous
Clinical Disorder
system problems. This is
because brain cells are unable to produce sufficient ATP (via the TCA
cycle) if the PDH complex
is inactive. Wernicke-Korsakoff, an encephalopathy-psychosis
syndrome due to thiamine deficiency, may be seen with alcohol abuse.
• Leigh syndrome (subacute necrotizing

encephalomyelopathy) is a rare, progressive neurological
disorder that is the result of defects in mitochondrial ATP
production, primarily as a result of
mutations in the PDH complex, the electron transport chain,
or ATP synthase.
Arsenic poisoning
• Arsenite (the trivalent form of arsenic) forms a stable

complex with the thiol (–SH) groups of lipoic acid,
making that compound unavailable to serve as a
coenzyme. When it binds to lipoic acid in the PDH
complex, pyruvate (and consequently lactate)
accumulates. Like pyruvate dehydrogenase deficiency,
this particularly affects the brain, causing neurologic
disturbances and death
The conversion of pyruvate to acetyl CoA
and
CO2:
 A. is reversible.
 B. involves the participation of lipoic acid.
 C. is activated when pyruvatedehydrogenas
(PDH,E1) of the pyruvate e
complex is phosphorylated by PDH dehydrogenas
kinase in
the e
presence of ATP.
 D. occurs in the cytosol.
 E. depends on the coenzyme biotin.

Correct answer = B.
 Lipoic acid is an intermediate acceptor of the
acetyl group formed in ther eaction.
 Pyruvate dehydrogenase complex catalyzes

an irreversible reaction that is inhibited when
the PDH (E1) component is phosphorylated.
 The enzyme complex is located in

the
mitochondrial matrix.
 Biotin is utilized by carboxylases.

Which one of the following conditions
decreases the oxidation of acetyl CoA by the
citric acid cycle?
 A. A low ATP/ADP ratio.

 B. A low NADH concentration due to rapid
oxidation to NAD+ through the respiratory
chain.
 C. A low NAD+/NADH ratio
 D. A high concentration of
AMP
 E. A low GTP/GDP ratio
Correct answer = C.
 A low NAD+/NADH ratio limits the rates of

the NAD+-requiring dehydrogenases.
 A low ATP/ADP or GTP/GDP ratio stimulates

the cycle.
 AMP does not directly affect the cycle.

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Lec.

first second third

 It is the final pathway where the oxidative metabolism of

 This oxidation provides energy for the production of the

 The cycle occurs totally in the

 The TCA cycle is an aerobic

thecycle functions in the glucose from the

Therefore, this cycle should not be viewed as a closed circle,

Pyruvate, the end product of aerobic glycolysis, must be

 This is accomplished by a specific pyruvate transporter that

Once in the matrix, pyruvate is converted to acetyl CoA by

a molecule of acetyl-CoA with

FAD succinyl CoA CH2 COO NADH+H+ NAD+ CH2 COO

② Serves as the crossroad for the

• The metabolism of glucose is representative of that of

 A. Regulation by activation and inhibition

(3) Isocitrate dehydrogenase

(4) -Ketoglutarate dehydrogenase

1. Effect of elevated ADP:

 Energy consumption as a result of

 Resulting increase in conc of ADP

 If ADP (or Pi) is present in limiting conc,

 Oxidation of NADH & FADH2 by ETC

 As NADH & FADH2 accumulate, their

thiamine pyrophosphate, TPP

• Leigh syndrome (subacute necrotizing

• Arsenite (the trivalent form of arsenic) forms a stable

 E. depends on the coenzyme biotin.

 Pyruvate dehydrogenase complex catalyzes

 The enzyme complex is located in

 Biotin is utilized by carboxylases.

 A. A low ATP/ADP ratio.

 A low NAD+/NADH ratio limits the rates of

 A low ATP/ADP or GTP/GDP ratio stimulates

 AMP does not directly affect the cycle.

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