Reactome | PC carboxylates PYR to OA

PC carboxylates PYR to OA

Stable Identifier

R-HSA-70501

Type

Reaction [transition]

Species

Homo sapiens

Compartment

mitochondrial matrix

Synonyms

PC catalyzes the carboxylation of PYR to form OA, ATP + hydrogencarbonate + pyruvate => ADP + H(+) + oxaloacetate + phosphate

ReviewStatus

5/5

Locations in the PathwayBrowser

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Metabolism (Homo sapiens)

- Aerobic respiration and respiratory electron transport (Homo sapiens)
  - Pyruvate metabolism (Homo sapiens)
    - PC carboxylates PYR to OA (Homo sapiens)
- Metabolism of carbohydrates and carbohydrate derivatives (Homo sapiens)
  - Glucose metabolism (Homo sapiens)
    - Gluconeogenesis (Homo sapiens)
      - PC carboxylates PYR to OA (Homo sapiens)

General

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Mitochondrial pyruvate carboxylase (PC) catalyzes the irreversible reaction of pyruvate (PYR), bicarbonate (HCO3-), and ATP to form oxaloacetate (OA), ADP, phosphate, (Pi), and H+. The enzyme is biotinylated and is active as a tetramer. The protein structure and function have been characterized in detail (Jitrapakdee et al., 2008; Jitrapakdee & Wallace, 1999; Lopez-Alonso et al., 2022). The reaction proceeds in two steps, with the biotin modification carboxylated first (Wexler et al., 1998). It is highly sensitive to activation by acetyl-CoA and gets inhibited by 2-oxoglutarate, L-malate, and L-glutamate (Scrutton & White, 1974; Jitrapakdee et al., 2008). Activation of PC by acetyl-CoA produced from lipolysis and leading to excess gluconeogenesis is the central mechanism of metabolic syndrome and diabetes (reviewed in Lao-On et al., 2018). Both normal and defective forms of the human enzyme have been described, with deficiency leading to lactic acidosis and potentially intellectual disability and death (MIM:266150; Carbone & Robinson, 2003; reviewed in Marin-Valencia et al., 2010).

Literature References

PubMed ID	Title	Journal	Year
12437512	Expression and characterization of a human pyruvate carboxylase variant by retroviral gene transfer Carbone, MA, Robinson, BH	Biochem J	2003
10229653	Structure, function and regulation of pyruvate carboxylase Jitrapakdee, S, Wallace, JC	Biochem J	1999
4826475	Purification and properties of human liver pyruvate carboxylase Scrutton, MC, White, MD	Biochem Med	1974
9585002	Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families Wexler, ID, Kerr, DS, Du, Y, Kaung, MM, Stephenson, W, Lusk, MM, Wappner, RS, Higgins, JJ	Pediatr Res	1998
36261450	CryoEM structural exploration of catalytically active enzyme pyruvate carboxylase López-Alonso, JP, Lázaro, M, Gil-Cartón, D, Choi, PH, Dodu, A, Tong, L, Valle, M	Nat Commun	2022
20598931	Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis Marin-Valencia, I, Roe, CR, Pascual, JM	Mol Genet Metab	2010
29362846	Roles of pyruvate carboxylase in human diseases: from diabetes to cancers and infection Lao-On, U, Attwood, PV, Jitrapakdee, S	J Mol Med (Berl)	2018
18613815	Structure, mechanism and regulation of pyruvate carboxylase Jitrapakdee, S, St Maurice, M, Rayment, I, Cleland, WW, Wallace, JC, Attwood, PV	Biochem J	2008