Pyruvate carboxylase
From Proteopedia
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| - | <StructureSection load='2qf7' size='340' side='right' caption='Pyruvate carboxylase complex with CoA, ATP-gamma-S,glycerol, Mg++ (green), Zn++ (grey) Cl- (green) (PDB code [[2qf7]])' scene=''> | + | <StructureSection load='2qf7' size='340' side='right' caption='Pyruvate carboxylase complex with CoA, ATP-gamma-S, glycerol, Mg++ (green), Zn++ (grey) Cl- (green) (PDB code [[2qf7]])' scene='93/939263/Cv/2'> |
==Function== | ==Function== | ||
| - | Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme (EC 6.4.1.1) of the ligase class that catalyzes (depending on the species) the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA). | + | Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme (EC 6.4.1.1) of the ligase class that catalyzes (depending on the species) the physiologically irreversible carboxylation of <scene name='39/392339/Cv1/11'>pyruvate</scene> to form <scene name='43/430893/Cv/3'>oxaloacetate</scene> (OAA). PC is a biotin-containing enzyme. PC is a tetrameric protein containing biotin carboxylase (BC), carboxyltransferase (CT), allosteric effector (acetyl-CoA) and biotin carboxyl carrier protein (BCCP) domains. PC is regulated by acetyl-CoA and Asp. The biotin moiety transfers the carboxyl group from the biotin carboxylase active site to the carboxyltransferase active site<ref>PMID:18613815</ref> . |
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| + | See also [[Major metabolic pathways converging on the citric acid cycle]]. | ||
==Disease== | ==Disease== | ||
| - | Mutations in the PC gene cause 3 types of clinical spectra. Type A and B are neonatal forms causing early death; type C causes mild intellectual delay<ref>PMID:30870574</ref> . | + | Mutations in the PC gene cause 3 types of clinical spectra. Type A and B are neonatal forms causing early death; type C causes mild intellectual delay<ref>PMID:30870574</ref>. Deregulation of PC expression is associated with type 2 diabetics and tumorgenesis in several cancers<ref>PMID:29362846</ref> . |
==Structural highlights== | ==Structural highlights== | ||
| - | The 3D structure of PC shows its 4 domains: BC, CT, allosteric effector and BCCP. | + | The 3D structure of PC shows its <scene name='93/939263/Cv/3'>4 domains: BC, CT, allosteric effector and BCCP</scene>. |
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| + | The <scene name='93/939263/Cv/7'>ATP moiety active site is in the BC domain and contains 2 Mg++ ions</scene>. Water molecules shown as red spheres. <scene name='93/939263/Cv/8'>Close up view of 2 Mg++ coordination sites</scene>. | ||
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| + | The <scene name='93/939263/Cv/9'>effector CoA is bound to the BC domain and the allosteric effector domain</scene><ref>PMID:17717183</ref>. | ||
==3D structures of pyruvate carboxylase== | ==3D structures of pyruvate carboxylase== | ||
Current revision
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References
- ↑ Jitrapakdee S, St Maurice M, Rayment I, Cleland WW, Wallace JC, Attwood PV. Structure, mechanism and regulation of pyruvate carboxylase. Biochem J. 2008 Aug 1;413(3):369-87. doi: 10.1042/BJ20080709. PMID:18613815 doi:http://dx.doi.org/10.1042/BJ20080709
- ↑ Coci EG, Gapsys V, Shur N, Shin-Podskarbi Y, de Groot BL, Miller K, Vockley J, Sondheimer N, Ganetzky R, Freisinger P. Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants in PC and analysis of the genotype-phenotype correlation. Hum Mutat. 2019 Jun;40(6):816-827. doi: 10.1002/humu.23742. Epub 2019 Apr 13. PMID:30870574 doi:http://dx.doi.org/10.1002/humu.23742
- ↑ Lao-On U, Attwood PV, Jitrapakdee S. Roles of pyruvate carboxylase in human diseases: from diabetes to cancers and infection. J Mol Med (Berl). 2018 Apr;96(3-4):237-247. doi: 10.1007/s00109-018-1622-0. Epub , 2018 Jan 23. PMID:29362846 doi:http://dx.doi.org/10.1007/s00109-018-1622-0
- ↑ St Maurice M, Reinhardt L, Surinya KH, Attwood PV, Wallace JC, Cleland WW, Rayment I. Domain architecture of pyruvate carboxylase, a biotin-dependent multifunctional enzyme. Science. 2007 Aug 24;317(5841):1076-9. PMID:17717183 doi:317/5841/1076
