citric acid cycle pathway - Rat Genome Database

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Keyword

CITRIC ACID CYCLE PATHWAY (PW:0000026)

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Description

The citric acid cycle, also known as the Krebs or tricarboxylic acid cycle (TCA), is considered a hub of cellular fuel metabolism. It consists of a series of eight reactions that oxidize the acetyl group of acetyl-CoA - the only precursor of the cycle - to two molecules of CO₂ while conserving the liberated energy in the reduced NADH and FADH₂ compounds. The stored electrons are passed to oxygen via the electron transport chain and the generated electrochemical gradien

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t is used to drive the ATP synthesis. The acetyl-CoA necessary to initiate the cycle is derived from pyruvate or from fatty acids and amino acid degradation. The cycle intermediates can also be derived from or fueled into other pathways. Oxaloacetate, alpha-ketoglutarate, succinyl-CoA and fumarate can be derived from the degradation of various amino acids. Oxaloacetate can be used for the biosynthesis of glucose and amino acids, alpha-ketoglutarate for the biosynthesis of amino acids and citrate provides the source for the cytosolic acetyl CoA in the fatty acids biosynthetic pathway. One round of the cycle gives rise to three molecules of NADH and one of FADH₂ (colored gold and as applicable, numbered); there is also one molecule of GTP or ATP produced (not shown). The oxaloacetate consumed in the first step is regenerated in the last step; the cycle can go on for as long as there are acetyl groups available. One turn of the cycle generates ~10 ATP molecules. Glucose oxidation requires two rounds of the cycle (glycolysis yields two pyruvate molecules whose oxidation produces two acetyl-CoAs). �More rounds of TCA cycle are necessary to complete fatty acid oxidation since their carbon skeleton is larger than the one of glucose. The flux of the cycle is controlled by the availability of substrates, product inhibition and competitive feedback inhibition. The cycle takes place in the mitochondrion. Since the metabolites are present in both the mitochondria and cytosol, the identification of rate-limiting steps is more difficult. The estimated free energy changes for the reactions point to three enzymes likely to function far from equilibrium: citrate synthase (step 1), isocitrate dehydrogenase (step 3) and oxoglutarate dehydrogenase (step 4) - the unidirectional reaction arrows in the diagram.Click to get to the entry for the molecule of the month, October 2012, at the Protein Data Bank which is dedicated to the structures of proteins/complexes in the eight reactions of the cycle. To see the ontology report for annotations, GViewer and download, click here [click to see the ontology report for associated GO term - GO:0006099, KEGG map - map00020 and related entry at Reactome - REACT_1046.3]...(less)

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citric acid cycle pathway
	Symbol	Object Name	GBrowse	Evidence	Chr	Start	Stop	Reference	Source
G	Acly	ATP citrate lyase		IEA	10	89,420,934	89,471,398	RGD:6907045	KEGG
G	Aco1	aconitase 1, soluble		IEA	5	57,536,675	57,591,765	RGD:6907045	KEGG
G	Aco2	aconitase 2, mitochondrial		IDA	7	120,223,788	120,266,944	RGD:2306877	RGD
G	Aco2	aconitase 2, mitochondrial		IEA	7	120,223,788	120,266,944	RGD:6907045	KEGG
G	Cs	citrate synthase		IDA	7	1,626,181	1,652,197	RGD:2306828	RGD
G	Cs	citrate synthase		IDA	7	1,626,181	1,652,197	RGD:2306877	RGD
G	Cs	citrate synthase		IEA	7	1,626,181	1,652,197	RGD:6907045	KEGG
G	Dlat	dihydrolipoamide S-acetyltransferase		IEA	8	53,989,491	54,014,779	RGD:6907045	KEGG
G	Dld	dihydrolipoamide dehydrogenase		IEA	6	49,185,188	49,205,894	RGD:6907045	KEGG
G	Dld	dihydrolipoamide dehydrogenase		ISS	6	49,185,188	49,205,894	RGD:2306878	RGD
G	Dlst	dihydrolipoamide S-succinyltransferase (E2 component of 2-oxo-glutarate complex)		IEA	6	109,156,751	109,180,537	RGD:6907045	KEGG
G	Dlst	dihydrolipoamide S-succinyltransferase (E2 component of 2-oxo-glutarate complex)		ISS	6	109,156,751	109,180,537	RGD:2306878	RGD
G	Fh	fumarate hydratase		IDA	13	91,329,837	91,355,722	RGD:2306828	RGD
G	Idh1	isocitrate dehydrogenase 1 (NADP+), soluble		IEA	9	63,769,401	63,790,622	RGD:6907045	KEGG
G	Idh2	isocitrate dehydrogenase 2 (NADP+), mitochondrial		IEA	1	135,876,052	135,895,373	RGD:6907045	KEGG
G	Idh3a	isocitrate dehydrogenase 3 (NAD+) alpha		IDA	8	58,135,412	58,156,019	RGD:2306828	RGD
G	Idh3a	isocitrate dehydrogenase 3 (NAD+) alpha		IEA	8	58,135,412	58,156,019	RGD:6907045	KEGG
G	Idh3B	isocitrate dehydrogenase 3 (NAD+) beta		IDA	3	117,892,614	117,897,633	RGD:2306828	RGD
G	Idh3B	isocitrate dehydrogenase 3 (NAD+) beta		IEA	3	117,892,614	117,897,633	RGD:6907045	KEGG
G	Idh3g	isocitrate dehydrogenase 3 (NAD), gamma		IDA	X	159,701,345	159,710,254	RGD:2306828	RGD
G	Idh3g	isocitrate dehydrogenase 3 (NAD), gamma		IEA	X	159,701,345	159,710,254	RGD:6907045	KEGG
G	Mdh1	malate dehydrogenase 1, NAD (soluble)		IEA	14	102,259,130	102,273,788	RGD:6907045	KEGG
G	Mdh2	malate dehydrogenase 2, NAD (mitochondrial)		IDA	12	22,021,302	22,034,257	RGD:2306828	RGD
G	Mdh2	malate dehydrogenase 2, NAD (mitochondrial)		IEA	12	22,021,302	22,034,257	RGD:6907045	KEGG
G	Ogdh	oxoglutarate (alpha-ketoglutarate) dehydrogenase (lipoamide)		IDA	14	87,022,994	87,090,768	RGD:2306877	RGD
G	Ogdh	oxoglutarate (alpha-ketoglutarate) dehydrogenase (lipoamide)		IEA	14	87,022,994	87,090,768	RGD:6907045	KEGG
G	Ogdh	oxoglutarate (alpha-ketoglutarate) dehydrogenase (lipoamide)		ISS	14	87,022,994	87,090,768	RGD:2306878	RGD
G	Ogdhl	oxoglutarate dehydrogenase-like		IEA	16	7,837,198	7,859,438	RGD:6907045	KEGG
G	Pc	pyruvate carboxylase		IEA	1	207,112,853	207,212,737	RGD:6907045	KEGG
G	Pck1	phosphoenolpyruvate carboxykinase 1 (soluble)		IEA	3	164,012,410	164,018,359	RGD:6907045	KEGG
G	Pck2	phosphoenolpyruvate carboxykinase 2 (mitochondrial)		IEA	15	33,671,834	33,680,613	RGD:6907045	KEGG
G	Pdha1	pyruvate dehydrogenase (lipoamide) alpha 1		IEA	X	55,899,491	55,913,319	RGD:6907045	KEGG
G	Pdha2	pyruvate dehydrogenase (lipoamide) alpha 2		IEA	2	238,983,103	238,984,651	RGD:6907045	KEGG
G	Pdhb	pyruvate dehydrogenase (lipoamide) beta		IEA	15	18,737,449	18,743,391	RGD:6907045	KEGG
G	Sdha	succinate dehydrogenase complex, subunit A, flavoprotein (Fp)		IEA	1	29,739,359	29,764,329	RGD:6907045	KEGG
G	Sdha	succinate dehydrogenase complex, subunit A, flavoprotein (Fp)		ISS	1	29,739,359	29,764,329	RGD:2306881	RGD
G	Sdhb	succinate dehydrogenase complex, subunit B, iron sulfur (Ip)		IEA	5	159,818,669	159,839,772	RGD:6907045	KEGG
G	Sdhb	succinate dehydrogenase complex, subunit B, iron sulfur (Ip)		ISS	5	159,818,669	159,839,772	RGD:2306881	RGD
G	Sdhc	succinate dehydrogenase complex, subunit C, integral membrane protein		IEA	13	87,014,569	87,035,239	RGD:6907045	KEGG
G	Sdhc	succinate dehydrogenase complex, subunit C, integral membrane protein		ISS	13	87,014,569	87,035,239	RGD:2306881	RGD
G	Sdhd	succinate dehydrogenase complex, subunit D, integral membrane protein		IEA	8	53,955,067	53,964,547	RGD:6907045	KEGG
G	Sdhd	succinate dehydrogenase complex, subunit D, integral membrane protein		ISS	8	53,955,067	53,964,547	RGD:2306881	RGD
G	Sucla2	succinate-CoA ligase, ADP-forming, beta subunit		IDA	15	54,214,262	54,267,830	RGD:2306915	RGD
G	Sucla2	succinate-CoA ligase, ADP-forming, beta subunit		IEA	15	54,214,262	54,267,830	RGD:6907045	KEGG
G	Suclg1	succinate-CoA ligase, alpha subunit		IDA	4	106,572,140	106,601,495	RGD:2306915	RGD
G	Suclg1	succinate-CoA ligase, alpha subunit		IEA	4	106,572,140	106,601,495	RGD:6907045	KEGG
G	Suclg2	succinate-CoA ligase, GDP-forming, beta subunit		IDA	4	129,995,856	130,276,182	RGD:2306915	RGD
G	Suclg2	succinate-CoA ligase, GDP-forming, beta subunit		IEA	4	129,995,856	130,276,182	RGD:6907045	KEGG
altered citric acid cycle pathway
	Symbol	Object Name	GBrowse	Evidence	Chr	Start	Stop	Reference	Source
G	Fh	fumarate hydratase		ISS	13	91,329,837	91,355,722	RGD:6907135	RGD
G	Sdhb	succinate dehydrogenase complex, subunit B, iron sulfur (Ip)		ISS	5	159,818,669	159,839,772	RGD:6907134	RGD
G	Sdhd	succinate dehydrogenase complex, subunit D, integral membrane protein		ISS	8	53,955,067	53,964,547	RGD:6907134	RGD

Additional Elements in Pathway:

(includes Gene Groups, Small Molecules, Other Pathways..etc.)

Object Type	Pathway Object	Pathway Object Description
Complex	alpha keto complex	alpha keto complex
Complex	Idh3 complex	isocitrate dehydrogenase complex
Complex	Sdh complex	succinate dehydrogenase complex
Complex	Scs Complex	Succinyl-CoA synthetase complex catalyzes the reversible interconversion of succinyl-CoA and succinate and releases GTP or ATP.
Protein	PDB, October 2012 molecule of the month, TCA cycle	The structures of proteins/complexes of the eight reactions of the cycle, at the Protein Data Bank (the link is also provided at the end of the description)

Pathway Gene Annotations

Disease Annotations Associated with Genes in the citric acid cycle pathway

Diseases/Genes

Genes/Diseases

Disease Terms	Gene Symbols
Carcinoma, Renal Cell	Fh , Sdhd , Sdhb
Congenital thrombotic disease, due to Protein C deficiency	Pc
Protein C Deficiency	Pc
Obesity	Idh1
Leigh Disease	Sdha , Dld
Reed's syndrome	Fh
Leiomyomatosis	Fh
Diabetes Mellitus, Type 2	Pck1
Hypoglycemia	Pck1 , Pck2
Hirschsprung Disease	Aco2
Cardiomyopathy, Dilated	Sdha
Maple Syrup Urine Disease	Dld
Pyruvate Carboxylase Deficiency Disease	Pc
Pyruvate Dehydrogenase Complex Deficiency Disease	Pdha1 , Pdhb
Alpha-ketoglutarate dehydrogenase deficiency	Ogdh
Alzheimer Disease	Pck1
Phosphoenolpyruvate carboxykinase deficiency	Pck1
Phosphoenolpyruvate carboxykinase 2 deficiency	Pck2
Leiomyomatosis and renal cell cancer, hereditary	Fh
Kidney Neoplasms	Fh
Gastrointestinal Stromal Tumors	Sdhb , Sdhc
Fumaric aciduria	Fh
Dentin Dysplasia	Acly
Glioma	Idh1
Brain Ischemia	Mdh2
Diabetes Mellitus, Experimental	Pck1
Heart Failure	Mdh2
Hyperglycemia	Pck1
Myocardial Infarction	Mdh2
Paraganglioma	Sdhd , Sdhb , Sdhc
Pheochromocytoma	Sdhd , Sdhb
Sleep Deprivation	Dlat
HYPERCHOLESTEROLEMIA, FAMILIAL	Fh
MITOCHONDRIAL DNA DEPLETION SYNDROME 9 (ENCEPHALOMYOPATHIC TYPE WITH METHYLMALONIC ACIDURIA)	Suclg1
MITOCHONDRIAL DNA DEPLETION SYNDROME 5 (ENCEPHALOMYOPATHIC WITH METHYLMALONIC ACIDURIA)	Sucla2
THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL RECESSIVE	Pc
D-2-HYDROXYGLUTARIC ACIDURIA 2	Idh2
Carcinoid Tumors, Intestinal	Sdhd
Leigh Syndrome, X-Linked	Pdha1
Carney-Stratakis Syndrome	Sdhd , Sdhb , Sdhc
Mitochondrial Complex II Deficiency	Sdha
Pyruvate Dehydrogenase E2 Deficiency	Dlat
Cowden-Like Syndrome	Sdhd , Sdhb

Pathway Annotations Associated with Genes in the citric acid cycle pathway

Pathways/Genes

Genes/Pathways

Pathway Terms	Gene Symbols
Alzheimer disease pathway	Sdha , Sdhd , Sdhb , Sdhc
Huntington disease pathway	Sdha , Sdhd , Sdhb , Sdhc
Parkinson disease pathway	Sdha , Sdhd , Sdhb , Sdhc
glycolysis/gluconeogenesis pathway	Pck1 , Pdha1 , Dlat , Pdha2 , Dld , Pck2 , Pdhb
citric acid cycle pathway	Acly , Aco1 , Fh , Idh1 , Idh3g , Mdh1 , Pc , Pck1 , Pdha1 , Idh3a , Mdh2 , Suclg1 , Dlat , Pdha2 , Cs , Aco2 , Sdha , Idh3B , Dld , Sdhd , Suclg2 , Sdhb , Sucla2 , Ogdhl , Pck2 , Pdhb , Sdhc , Dlst , Ogdh , Idh2
fatty acid biosynthetic pathway	Acly
electron transport chain pathway	Sdha , Sdhd , Sdhb , Sdhc
pyruvate metabolic pathway	Mdh1 , Pc , Pck1 , Pdha1 , Mdh2 , Dlat , Pdha2 , Dld , Pck2 , Pdhb
glycine, serine and threonine metabolic pathway	Dld
tryptophan metabolic pathway	Ogdh , Ogdhl
glyoxylate and dicarboxylate metabolic pathway	Aco1 , Mdh1 , Mdh2 , Cs , Aco2
propanoate metabolic pathway	Suclg1 , Suclg2 , Sucla2
butanoate metabolic pathway	Pdha1 , Pdha2 , Pdhb
valine, leucine and isoleucine degradation pathway	Dld
valine, leucine and isoleucine biosynthetic pathway	Pdha1 , Pdha2 , Pdhb
lysine degradation pathway	Dlst , Ogdh , Ogdhl
glutathione metabolic pathway	Idh1 , Idh2
insulin signaling pathway	Pck1 , Pck2
glycolysis pathway	Pck1 , Pdha1 , Dlat , Pdha2 , Dld , Pck2 , Pdhb
gluconeogenesis pathway	Pc , Pck1 , Pdha1 , Dlat , Pdha2 , Dld , Pck2 , Pdhb
forkhead class A signaling pathway	Pck1
renal cell cancer pathway	Fh , Sdhd , Sdhb
oxidative phosphorylation pathway	Sdha , Sdhd , Sdhb , Sdhc
altered citric acid cycle pathway	Fh , Sdhd , Sdhb
eicosanoid signaling pathway via peroxisome proliferator-activated receptor gamma	Pck1 , Pck2
folate cycle metabolic pathway	Dld

References Associated with the citric acid cycle pathway:

Ontology Path Diagram:

Import into Pathway Studio:

citric acid cycle pathway.gpp