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Detoxicol

SDLS 2008
Medicine for the intoxicated
File Created on 8/31/2004 03:30 PM Topic: TCA Cycle
Transcriber(s): Audrey, Mark longus, Henry, Lance Lecturer: Dr. Dalisay Chionglo-Sy
Editors: JC Tayco, Mark Lomboy, Pre Ausan, Lulu Velazco No. of pages: 5

The CITRIC ACID CYCLE 2 . glutamate dehydrogenase – in the


Known as: TRICARBOXYLIC ACID CYCLE (TCA liver
CYCLE, KREBS CYCLE).
Also a major pathway for the inter conversion GLUT + NADP + H 2O  α -
of the metabolites arising from the KETOGLUTARATE + NADPH + NH4
transamination and deamination of
amino acids.
PEP carboxykinase – in heart and skeletal
 oxidize acetyl residues(as Acetyl CoA) and
muscle.
reduce coenzymes that upon reoxidation are
linked to the formation of ATP.
PEP + CO2 + GDP  OAA + GTP
 final common pathway for the aerobic
oxidation of Carbohydrates, Lipid and
Protein, because glucose, fattyacids and
most amino acids are metabolised to Acetyl- Malic enzyme - in many tissues
CoA or intermediates of the cycle. (able to
donate substrate to the TCA cycle). PYRUVATE + HCO3 + NADPH 
Found in: MITOCHONDRIAL MATRIX (Location of MALATE + NADP
enzymes of TCA, also the site of enzymes
of the respiratory chain. TCA PRODUCTS PER REVOLUTION
 Release of 2 moles of CO2
FUNCTIONS:
 Regeneration of one mole OXAA
1.Catabolic  Generation of 9 moles ATP (via
 Transfers electron pairs (potential energy) oxidative phosphorylation)
from Acetyl Coenzyme A to NAD and FAD.  Synthesis of one high energy
phosphate (as GTP)

CH3CO-CoA + 3NAD + FAD + GDP + Pi


TCA CYCLE REGULATION
2CO2 + 3NADH + FADH2 + GTP + CoA
Citrate synthase
- acetyl CoA + OXAA = citrate
- allosteric inhibitor: ATP
9ATP= Oxidative Phosphorylation
- increases Km for acetyl CoA
1ATP= Substrate level Phosphorylation
Isocitrate dehydrogenase
2. Anabolic
Specific metabolites used for - converts isocitrate to α -ketoglutarate
fatty acid synthesis
- gluconeogenesis - allosteric activator: ADP
- synthesis of heme
- amino acid synthesis - inhibitors: ATP,NADH
*collectively known as Amphibolic(functions in both
oxidative and synthetic process) 3. α -ketoglutarate

ANAPLEROTIC REACTIONS - converts α -ketoglutarate to succinyl


 are “filling-up” reactions Coa
 replenishment of intermediates to ensure
continuity of cycle. - inhibitors: SUCCINYL COENZYME A and
 not part of TCA cycle, it only produce NADH
intermediates for TCA cycle.
1. pyruvate carboxylase – in the Important Terms:
liver and kidney. • Oxidation of Acetyl-CoA- Coenzymes are
- most important anaplerotic reactions. reduced and subsequently reoxidized in the
respiratory chain, linked to the formation of
Pyruvate + HCO3 + ATP  OXAA + ADP + ATP
Pi -Aerobic process
• Citrate synthase- enzymes that catalyze the
initial reaction between Acetyl-CoA and
Oxaloacetate to form citrate.
• Aconitase- Aconitase Hydratase
• Lyase-enzyme that isomerizes citrate to
isocitrate. REACTION SEQUENCE:
• Isocitrate Dehydrogenase- enzyme that First step in the reaction sequence that converts
catalyzes the dehydrogenation of Isocitrate Pyruvate to Carbon Dioxide and Acetyl-CoA.
to form Oxalosuccinate. • is catalyzed by Pyruvate Dehydrogenase
• α -Ketoglutarate dehydrogenase complex- • requires Thiamine Pyrophosphate is a
requires the same cofactors as the pyruvate coenzyme (metabolite of vitamin B1)
dehydrogenase complex-thiamine • coenzyme not covalently bonded to the
diphosphate, lipoate, NAD+, FAD and CoA- enzyme, held together by noncovalent
and results in the formation of succinyl-CoA. interactions.
• Arsenite- inhibits the reactions(oxidative • Mg2+ required
decarboxylation); causing substrate Alpha- • in Pyruvate Dehydrogenase reaction a –Keto
Ketoglutarate to accumulate. acid, pyruvate,loses Carbon Dioxide; the
• Succinate thiokinase- succinyl-CoA synthase remaining two carbon unit becomes
-converts Succinyl-CoA to Succinate. covalently bonded to TPP.

*Converted to Oxaloacetate by malate Second step of the reaction is catalyzed by


Dehydrogenase, a reaction requiring NAD+. Dihydrolipoyl Transacetylase.
• Dihydrolipoyl Transacetylase requires Liopic
B-Vitamins in Citric Acid cycle: Acid as a coenzyme.
1. Riboflavin- in the form of flavin adenine • Lipoic acid is covalently bonded to the
dinucleotide. enzyme.
-cofactor in the Alpha- Ketoglutarate • The two carbon unit that originally came
dehydrogenase complex and in succinate from pyruvate is transferred from the
dehydrogenase. Thiamine Pyrophosphate to the Lipoic acid,
2. Niacin-in the form of nicotinamide adenine in the process a hydroxyl group is oxidized
dinucleotide(NAD). to produce an Acetyl group.
-Coenzyme for the three dehydrogenases in • Disulfide group of Lipoic acid is the oxidizing
the cycle- Isocitrate dehydrogenase, Alpha- agent, which itself reduced, the product is a
Ketoglutarate dehydrogenase and Malate Thiolester.
dehydrogenase. • Acetyl group is noncovalently bonded to the
3. Thiamine- as thiamine diphosphate lipoic acid by a thiolester linkage.
-enzyme for decarboxylation in the Alpha-
Ketoglutarate dehydrogenase reaction. Third step of the reaction Is also catalyzed by
4. Pantothenic Acid-part of coenzyme A Dihydrolipoyl Transacetylase.
-cofactor attached to active carboxylic acid
• a molecule of CoA-Sh attacks the Thiolester
residues such as Acetyl-CoA are Succinyl-
linkage, the acetyl groupis transferred to it.
CoA.
• Acetyl group remains bound to the
Individual Reactions of the Citric Acid Cycle: Thiolester linkage, this time as Acetyl-CoA
rather than Esterified to Lipoic acid.
 Conversion of Pyruvate to Acetyl-CoA
 Pyruvate Dehydrogenase Complex • the reaction of pyruvate and CoA-SH has non
-Enzyme reach the stage of the products,CO2 and
-Responsible for conversion of Pyruvate Acetyl-CoA, but the lipoic acid coenzyme is
to Carbon Dioxide and Acetyl portion in a required form.
of Acetyl-CoA.
 CoA Molecule- has –Sh group at one end Fourth step- the enzyme Dihydrolipoyl
where Acetyl group is attached. Dehydrogenase reoxidezes the reduced lipoic acid
from sulfhydryl to the disulfide form.
 Acetyl-CoA- is a Thiolester with a sulfur
atom, replacing oxygen of the usual
THE CITRIC ACID CYCLE PROPER:
carboxylic ester.
 Thiolester- high energy compound
Step 1:Formation of Citrate
 CoA is a Thiol(Sulfur[THIO] analog of an
alcohol)  Reaction of Acetyl-CoA and Oxaloacetate to
form citrate and CoA-SH(Reaction is called
*Hydrolysis of esters release energy to drive condensation).
reactions.  condensation is followed by the hydrolysis of
citryl-CoA to give citrate and CoA-SH.
Enzymes that makeup the Pyruvate  reaction catalyzed by citrate
Dehydrogenase Complex: synthase(Condensing enzyme).
 Pyruvate Dehydrogenase  Citrate Synthase-Allosteric enzyme
 Dihydrolipoyl Transacetylase  Inhibitors= ATP, NADH and Succinyl-CoA.
 Dihydrolipoyl Dehydrogenase =is a feedback control mechanism.

 Lipoic Acid-compound that has di-


sulfide group in its oxidized form
and two sulfhydryl groups in its
reduced form.
-is a Vitamin
-formation of Thiolester
linkage with the acetyl group before it
is transferred to Acetyl-CoA.
Step 2: Isomerization of citrate to isocitrate  In the reaction mechanism, a phosphate
 catalyzed by Aconitase, is the isomerization group covalently bonded to the enzyme
of citrate to isocitrate. is directly transferred to GDP.
 requires Fe2+  The energy required for the
 Isocitrate has four possible isomers, only one phosphorylation of GTP is provided by
produced in this reaction. the Hydrolysis of Succinyl-CoA to Produce
Succinate and CoA.
 removal of H2O molecule from citrate to
produce cis-Aconitase, and then H2O is added *The enzyme nucleoside di-phosphate kinase
back to the cis-Aconitase to give isocitrate. catalyze the transfer of a phosphate
 There is some evidence that citrate is group from GTP to ADP to give GDP and
completed to the Fe(II). ATP.

Step 3: Formation of Alpha –Ketoglutarate and


CO2 first oxidation.
 is the Decarboxylation of citrate to isocitrate Step 6: Formation of Fumarate-FAD-Linked
to Alpha-Ketoglutarate and CO2.
Oxidation
 This reaction is the first of the two oxidative
 Succinate is Oxidized to fumarate, A
Decarboxylation of CTA cycle; enzyme that
reaction that is catalyzed by the enzyme
catalyze it is Isocitrate Dehydrogenase.
Succinate Dehydrogenase(Integral
Steps:
protein of the inner mitochondrial
-First, Isocitrate is to oxidezed to oxalo
membrane).
succinate.
-Second, Oxalosuccinate is decarboxylated
and the CO2 and Alpha-Ketoglutarate are
released.
-first of the reactions in which NADH
is produced.
*Inhibited by ATP and NADH, and activated by ADP
and NAD+

Step 7:Formation of L-Malate


 catalyzed by the enzyme Fumarase.
 water is added across the double bond of
Fumarate in the hydration reaction to
give Malate.
Step 4: Formation of Succinyl-CoA are formed
from Alpha-Ketoglutarate and CoA.
 Carbondioxide and Succinyl-CoA are formed
from Alpha-KetoGlutarate and CoA.
 Catalyzed by as enzyme as enzyme system
called Alpha-Ketoglutarate Dehydrogenase
complex.

Akala mo may greatings noH!


(wrong spelling pa eh dapat ito: Grit-engs) –ed.
moi
Kala mo may chisms!
Masydo na kyong CHISMOSA!(smiling face)
FINAL STAGES OF CITRIC ACID CYCLE - SUCCINATE
IS CONVERTED TO OXALOACETATE(Conversion of
methylene group to a Carbonyl group)
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0919-5060405.
Step 5: Formation of Succinate MM.
*LOOK FOR
 the thiolesterbond of succinyl-CoA is
hydrolyzed to produced succinate and
First come, first served
CoA-SH, an accompanying reaction is the
Phosphorylation of GDP to GTP.
basis! Hurry! Avail now!
 is catalyzed by Succinyl-CoA Synthase.