Transcript Tricarboxylic Acid Cycle

Siti Annisa Devi Trusda
Biochemistry Department
Overview
final pathway where oxidative metabolism of CH, AA,
FAcarbon skeleton : CO2 & H2O
provides energy (ATP)
occurs in mitochondriain close proximity to
reactions of electron transport
 AerobicO2 required as the final electron acceptor
 Participates in synthetic rx/: formation of glucose from
carbon skeleton of some AA
 Intermediates of the TCA cycle can also be synthesized
by the catabolism of some amino acids
a traffic circle with compounds entering and leaving as
required
REACTION OF THE TCA CYCLE
 Pyruvate, the product of glycolysis, is converted to
acetyl-CoA, the starting material for the citric acid
cycle, by the pyruvate dehydrogenase complex.
 The PDH complex is composed of multiple copies of
three enzymes:
 pyruvate dehydrogenase, E1 (with its bound cofactor TPP);
 dihydrolipoyl transacetylase, E2 (with its covalently
bound lipoyl group)
 dihydrolipoyl dehydrogenase, E3 (with its cofactors FAD
and NAD).
E1 catalyzes the decarboxylation of
pyruvate hydroxyethyl -TPP, then the
oxidation of the hydroxyethyl group acetyl
group.
 E2 catalyzes the transfer of the acetyl group
to coenzyme A, forming acetyl-CoA.
 E3 catalyzes the regeneration of the
disulfide(oxidized) form of lipoate;
electrons pass first to FAD, then to NAD.

The Pyruvate Dehydrogenase Complex Requires
Five Coenzymes
 The combined dehydrogenation and decarboxylation of
pyruvate to the acetyl group of acetyl-CoA requires the
sequential action of
 3 different enzymes
 5 different coenzymes or prosthetic groups
 thiamine pyrophosphate (TPP),
 flavin adenine dinucleotide (FAD),
 coenzyme A (CoA, sometimes denoted CoA-SH, to emphasize
the role of the OSH group),
 nicotinamide adenine dinucleotide (NAD)
 lipoate.
 4 different vitamins required in human nutrition are vital
components of this system: thiamine (inTPP), riboflavin
(in FAD), niacin (in NAD), and pantothenate (in CoA).
Pyruvate Dehydrogenase
Deficiency
 congenital lactic acidosis
 inability to convert pyruvate to acetyl CoA
 Pyruvate to be shunted to lactic acid via lactate




dehydrogenase
Severe : Neonatal death
Moderate: psychomotor retardation w/ damage of
cerebral cortex, basal ganglia, brainstemdeath in
infancy
Third form: episodic ataxia induced by Ch rich meal
No treatment available ketogenic diet
Mechanism of Arsenic Poisoning
 Arsenic inhibits enzymes that require lipoic acid as
cofactor : pyruvate dehydrogenase, α-ketoglutarate
dehydrogenase.
 Arsenite forms a stable complex with the thiol (SH) group of lipoic acidunavailable to serve as
coenzyme
 If it binds to lipoic acid in the pyruvate
dehydrogenase complex, pyruvate (and lactate)
accumulate ≈ pyruvate dehydrogenase complex
deficiency neurologic distrubance - death
The Citric Acid Cycle Has 8 Steps
1. Formation of Citrate
2. Formation of Isocitrate via cis-Aconitate
3. Oxidation of isocitrate to α-ketoglutarate
+CO2
4. Oxidation of α-ketoglutarate to succinyl coA+
CO2
5. Conversion of succinyl coA to succinate
6. Oxidation of succinate to fumarate
7. Hydration of fumarate to malate
8.Oxidation of malate to oxaloacetate
 Products of one turn of the citric acid cycle.
At each turn of the cycle(each molecule of acetyl coA), 3
NADH (9 ATP), 1 FADH2(2 ATP), 1GTP (1 ATP), and
two CO2 are released in oxidative decarboxylation
reactions 12 ATP
Citric Acid Cycle Components Are Important
Biosynthetic Intermediates
 The citric acid cycle is an amphibolic pathwayboth
catabolic and anabolic processes.
 Besides its role in the oxidative catabolism of
carbohydrates, fatty acids, and amino acids, the cycle
provides precursors for many biosynthetic
pathways through reactions that served the same
purpose in anaerobic ancestors.
 α–Ketoglutarate and oxaloacetate can serve as
precursors of the amino acids aspartate and glutamate
by simple transamination
 Through aspartate and glutamate, the carbons of
oxaloacetate and α–ketoglutarate are then used to
build other amino acids, as well as purine and
pyrimidine nucleotides.
 Oxaloacetate is converted to glucose in
gluconeogenesis
 Succinyl-CoA is a central intermediate in the synthesis
of the porphyrin ring of heme groups, which serve as
 oxygen carriers (in hemoglobin and myoglobin)
 electron carriers (in cytochromes)
 Citrate produced in some organisms is used
commercially for a variety of purposes
Regulation of the Citric Acid Cycle
 The overall rate of the citric acid cycle is controlled by
 rate of conversion of pyruvate acetyl-CoA
 flux through citrate synthase, isocitrate dehydrogenase, & ketoglutarate dehydrogenase.
 These fluxes are largely determined by the concentrations
of substrates and products:
 the end products ATP and NADH are inhibitory
 the substrates NAD and ADP are stimulatory.
 The production of acetyl-CoA for the citric acid cycle
by the PDH complex is :
 inhibited allosterically by metabolites that signal a
sufficiency of metabolic energy (ATP, acetyl-CoA,
NADH, and fatty acids)
 stimulated by metabolites that indicate a reduced
energy supply (AMP, NAD, CoA).
HATURNUHUN….
LIKE ALWAYS, A SIMPLE QUIZ ;p
 Reaksi pertama yang terjadi untuk masuk ke dalam
siklus Krebs adalah perubahan…….. menjadi……..
 Produk dari satu putaran siklus Krebs adalah….., ………,
dan……….. dengan jumlah energi yang dihasilkan
sebanyak……..
 Defisiensi enzim piruvat dehidrogenase
mengakibatkan penyakit……..
 Berikan satu contoh komponen dalam siklus Krebs
yang menjadi zat antara biosintesis zat lain!