Pyruvate carboxylase
Pyruvate carboxylase | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Pyruvate carboxyltransferase | |||||||||
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Identifiers | |||||||||
Symbol | PYR_CT | ||||||||
Pfam | PF00682 | ||||||||
InterPro | IPR000891 | ||||||||
PROSITE | PDOC50991 | ||||||||
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Pyruvate carboxylase | |||||||
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Identifiers | |||||||
Symbol | PC | ||||||
Chr. 11 q11-q13.1 | |||||||
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PC | ||||||||||||||||||||||||||||||||||||||||
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Wikidata | ||||||||||||||||||||||||||||||||||||||||
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Pyruvate carboxylase (PC) encoded by the gene PC is an
The reaction it catalyzes is:
- pyruvate + HCO−
3 + ATP → oxaloacetate + ADP + P
It is an important anaplerotic reaction that creates oxaloacetate from pyruvate. The enzyme is a mitochondrial protein containing a biotin prosthetic group,[1] requiring magnesium or manganese and acetyl-CoA.
Pyruvate carboxylase was first discovered in 1959 at Case Western Reserve University by M. F. Utter and D. B. Keech.[6][7] Since then it has been found in a wide variety of prokaryotes and eukaryotes including fungi, bacteria, plants, and animals.[8] In mammals, PC plays a crucial role in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitters, and in glucose-induced insulin secretion by pancreatic islets. Oxaloacetate produced by PC is an important intermediate, which is used in these biosynthetic pathways.[9] In mammals, PC is expressed in a tissue-specific manner, with its activity found to be highest in the liver and kidney (gluconeogenic tissues), in adipose tissue and lactating mammary gland (lipogenic tissues), and in pancreatic islets. Activity is moderate in brain, heart and adrenal gland, and least in white blood cells and skin fibroblasts.[10]
Structure
Structural studies of PC have been conducted by
Pyruvate carboxylase uses a covalently attached biotin cofactor which is used to catalyze the ATP– dependent carboxylation of pyruvate to oxaloacetate in two steps. Biotin is initially carboxylated at the BC active site by ATP and bicarbonate. The carboxyl group is subsequently transferred by carboxybiotin to a second active site in the CT domain, where pyruvate is carboxylated to generate oxaloacetate. The BCCP domain transfers the tethered cofactor between the two remote active sites. The allosteric binding site in PC offers a target for modifiers of activity that may be useful in the treatment of obesity or type II diabetes, and the mechanistic insights gained from the complete structural description of RePC (R. etli) permit detailed investigations into the individual catalytic and regulatory sites of the enzyme.[13]
Reaction mechanism
The reaction mechanism can be subdivided into two partial reactions (see figure to the right). In the first reaction,
Function
During
Very high levels of PC activity, together with high activities of other gluconeogenic enzymes including
Aside from the role of PC in gluconeogenesis, PC serves an anaplerotic role (an enzyme catalyzed reaction that can replenish the supply of intermediates in the citric acid cycle) for the tricarboxylic acid cycle (essential to provide oxaloacetate), when intermediates are removed for different biosynthetic purposes.
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
Regulation
Pyruvate carboxylase is allosterically regulated by acetyl-CoA, Mg-ATP, and pyruvate.[20]
Clinical significance
As a crossroad between carbohydrate and lipid metabolism, pyruvate carboxylase expression in gluconeogenic tissues, adipose tissues and pancreatic islets must be coordinated. In conditions of over nutrition, PC levels are increased in pancreatic β-cells to increase pyruvate cycling in response to chronically elevated levels of glucose.[21] In contrast, PC enzyme levels in the liver are decreased by insulin;[22] during periods of overnutrition adipocyte tissue is expanded with extreme expression of PC and other lipogenic enzymes.[10][23] Hepatic control of glucose levels is still regulated in an over nutrition situation, but in obesity induced type 2 diabetes the regulation of peripheral glucose levels is no longer under regulation of insulin. In
A
See also
References
- ^ PMID 18613815.
- ^ a b c GRCh38: Ensembl release 89: ENSG00000173599 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024892 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 13840551.
- PMID 762171.
- ^ S2CID 850667.
- ^ PMID 12150961.
- ^ PMID 8687459.
- PMID 14993673.
- ^ PMID 19523900.
- ^ S2CID 34738991.
- PMID 19635791.
- PMID 1948033.
- S2CID 10376355.
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- PMID 10342812.
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- PMID 28271481.
- PMID 15507531.
- PMID 16601267.
- PMID 1375435.
- PMID 8866570.
- PMID 8666138.
- PMID 12438314.
- ^ PMID 11796484.
- PMID 15073188.
- PMID 11916915.
- PMID 11781146.
- S2CID 21367897.