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By : Nuniek Herdyastuti Pebruari - 2013

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is oxidized to acetyl-CoA and CO2 by the pyruvate dehydrogenase (PDH) complex.3/1/2013 CELLULAR RESPIRATION OCCURS IN THREE MAJOR STAGES :    Organic fuel molecules glucose. derived from glucose and other sugars by glycolysis. giving up protons (H) and electrons PRODUCTION OF ACETYL-COA (ACTIVATED ACETATE) . of a multienzyme complex. These reduced coenzymes are themselves oxidized. The acetyl groups are fed into the citric acid cycle. three enzymes located in the mitochondria of eukaryotic cells and in the cytosol of prokaryotes. fatty acids. Thiamine-deficient animals are unable to oxidize pyruvate normally (Brain)  Beriberi is characterized by loss neural function 2 .    Pyruvate. four derived from vitamins. Five cofactors. The PDH complex is a classic. the energy released is conserved in the reduced electron carriers NADH and FADH2. participate in the reaction mechanism. and some amino acids are oxidized to yield twocarbon fragments in the form of the acetyl group of acetylcoenzyme A (acetyl-CoA). which enzymatically oxidizes them to CO2 . a cluster of enzymes.

coenzyme A (CoA sometimes denoted CoA-SH) and lipoate 4 different vitamins required in human nutrition are vital components of this system : thiamine (in TPP). 5 coenzyme (prosthetic groups) : thiamine pyrophosphate (TPP). dihydrolipoyl transacetylase (E2). niacin (in NAD). flavin adenine dinucleotide (FAD). riboflavin (in FAD).3/1/2013 Coenzyme A (Co-A) Piruvat dehidrogenase   Complex enzyme : pyruvate dehydrogenase (E1). and pantothenate (in CoA) 3 . and dihydrolipoyl dehydrogenase (E3).

dihydrolipoyl transacetylase (E2). undergoing decarboxylation to the hydroxyethyl derivative The transfer of 2 electrons and the acetyl group from TPP to the oxidized form of the lipoyllysyl group of the core enzyme. to form the acetyl thioester of the reduced lipoyl group Transesterification in which the OSH group of CoA replaces the OSH group of E2 to yield acetyl-CoA and the fully reduced (dithiol) form of the lipoyl group 4 .3/1/2013 Oxidative decarboxylation of pyruvate to acetyl-CoA by the PDH complex Pyruvate reacts with the bound thiamine pyrophosphate (TPP) of pyruvate dehydrogenase (E1).

The enzyme complex is now ready for another catalytic cycle. the entire set of reactions of the citric acid cycle takes place in mitochondria (Eugene Kennedy & Albert Lehninger. restoring the oxidized form of the lipoyllysyl group of E2  the reduced FADH2 of E3 transfers a hydride ion to NAD. forming NADH.  Reactions of the Citric Acid Cycle     Citric acid cycle. 1948) In each turn of the cycle.3/1/2013 Dihydrolipoyl dehydrogenase (E3) promotes transfer of two hydrogen atoms from the reduced lipoyl groups of E2 to the FAD prosthetic group of E3. one acetyl group (two carbons) enters as acetyl-CoA and two molecules of CO2 The reaction is a circular not a linear 5 . also called the tricarboxylic acid (TCA) cycle or the Krebs cycle (after its discoverer 1937) In eukaryotes.

catalyzed by citrate synthase It rapidly undergoes hydrolysis to free citrate and CoA (liberated in this reaction is recycled to participate in the oxidative decarboxylation of another molecule of pyruvate by the PDH complex) 6 .3/1/2013 The Citric Acid Cycle Has Eight Steps 1 Formation of Citrate The condensation of acetyl-CoA (methyl carbon) with oxaloacetate (carbonyl groups) to form citrate.

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aconitate hydratase) catalyzes the reversible transformation of citrate to isocitrate. through the intermediary formation of the tricarboxylic acid cis-aconitate Aconitase contains an ironsulfur center . Formation of Isocitrate via ciscis-Aconitate An aconitase (more formally.3/1/2013 II. 8 . which acts both in the binding of the substrate at the active site and in the catalytic addition or removal of H2O.

3/1/2013 Isocitrate dehydrogenase catalyzes oxidative decarboxylation of isocitrate to form  –ketoglutarate Mn2+ in the active site interacts with the carbonyl group of the intermediate oxalosuccinate -ketoglutarate is converted to succinyl-CoA and CO2 by the action of the -ketoglutarate dehydrogenase complex NAD serves as electron acceptor and CoA as the carrier of the succinyl 9 .

to form ATP (or GTP) 10 . the enzyme itself becomes phosphorylated at a His residue in the active site This phosphoryl group. is transferred to ADP (or GDP) group transfer potential.3/1/2013 The enzyme that catalyzes this reversible reaction iscalled succinyl-CoA synthetase or succinic thiokinase.

Hidra Hidrat tion of fumarat fumarate e to malat malate e The reversible hydration of fumarate to malate is catalyzed by Fumarase (fumarat hidratase) The enzyme is highly stereospecific. Oxidation of Succinate to Fumarate The succinate formed from succinylCoA is oxidized to fumarate by the flavoprotein succinate dehydrogenase Malonate is a strong competitive inhibitor of succinate dehydrogenase VII. but not the cis double bond maleate (cis isomer of fumarate) 11 .3/1/2013 VI. it catalyzed hydration of the trans double bond of fumarate.

3/1/2013 VIII. Ox Oxida idat tion of malat malate e to oxa xaaloa aloac cetat etate e L-malate dehydrogenase catalyzed oxidation of Lmalate to oxaloasetate This keeps the concentration of oxaloasetate in the cell extremely low (10-6 M) Product Produ ct of the one turn of the citric acid cycle 12 .

3/1/2013 Role of the citric acid cycle in anabolism Regulation of citric acid cycl cycle 13 .

coenzyme-A. DNA. ATP. NADH. reducing NADP to NADPH and producing pentose phosphates. skin. intestinal mucosa : penthose  RNA. needed for reductive biosynthesis Oxidative and dekarboxylation at C-1 of glucose 6-phosphate. FADH2 The essential product of the pentose phosphate pathway is not the pentoses but the electron donor NADPH. NADPH provides reducing power for biosynthetic reactions. and ribose 5-phosphate is a precursor for nucleotide and nucleic acid synthesis 14 .3/1/2013 Penthose Phosphate pathways Penthose Phosphate       Oxidation of glucose 6-phosphate to pentose phosphates by the pentose phosphate pathway (also called the phosphogluconate pathway or the hexose monophosphate pathway Glucose 6-P  penthose phosphate Bone marrow.

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