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12-439: (S)-Methylmalonyl-CoA cannot be directly utilized by animals. It is acted upon by a racemase , yielding (R)-methylmalonyl-CoA, which is then converted into succinyl-CoA by methylmalonyl-CoA mutase (one of the few metabolic enzymes which requires vitamin B12 as a cofactor). Succinyl-CoA, a Krebs cycle intermediate, is further metabolized into fumarate , then malate , and then oxaloacetate . Oxaloacetate may be transported into

24-465: A 750 kDa alpha(6)-beta(6)-dodecamer. (Only approximately 540 kDa is native enzyme. ) The alpha subunits are arranged as monomers, decorating the central beta-6 hexameric core. Said core is oriented as a short cylinder with a hole along its axis. The alpha subunit of PCC contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains. A domain known as the BT domain is also located on

36-471: A multimer is formed from polypeptides produced by two different mutant alleles of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. In such a case, the phenomenon is referred to as intragenic complementation . PCC is a heteropolymer composed of α and β subunits in a α 6 β 6 structure. Mutations in PCC, either in

48-464: A phosphate group from either propionyl-CoA or ATP reacts with an essential arginine residue in the active site during catalysis. Later (2004), it was suggested that Arginine-338 serves to orient the carboxyphosphate intermediate for optimal carboxylation of biotin. The KM values for ATP, propionyl-CoA, and bicarbonate has been determined to be 0.08 mM, 0.29 mM, and 3.0 mM, respectively. The isoelectric point falls at pH 5.5. PCC's structural integrity

60-413: A separate gene: A deficiency is associated with propionic acidemia . PCC activity is the most sensitive indicator of biotin status tested to date. In future pregnancy studies, the use of lymphocyte PCC activity data should prove valuable in assessment of biotin status. When multiple copies of a polypeptide encoded by a gene form an aggregate, this protein structure is referred to as a multimer. When

72-524: Is conserved over the temperature range of -50 to 37 degrees Celsius and the pH range of 6.2 to 8.8. Optimum pH was shown to be between 7.2 and 8.8 without biotin bound. With biotin, optimum pH is 8.0-8.5. The normal catalytic reaction mechanism involves a carbanion intermediate and does not proceed through a concerted process. Figure 3 shows a probable pathway. The reaction has been shown to be slightly reversible at low propionyl-CoA flux. Human propionyl-CoA carboxylase contains two subunits, each encoded by

84-542: Is hydrophobic and highly conserved. Biotin and propionyl-CoA bind perpendicular to each other in the oxyanion hole -containing active site. The native enzyme to biotin ratio has been determined to be one mole native enzyme to 4 moles biotin. The N1 of biotin is thought to be the active site base. Site-directed mutagenesis at D422 shows a change in the substrate specificity of the propionyl-CoA binding site, thus indicating this residue's importance in PCC's catalytic activity. In 1979, inhibition by phenylglyoxal determined that

96-522: The alpha subunit and is essential for interactions with the beta subunit. The 8-stranded anti-parallel beta barrel fold of this domain is particularly interesting. The beta subunit contains the carboxyltransferase (CT) activity. The BC and CT sites are approximately 55 Å apart, indicative of the entire BCCP domain translocating during catalysis of the carboxylation of propionyl-CoA . This provides clear evidence of crucial dimeric interaction between alpha and beta subunits. The biotin-binding pocket of PCC

108-401: The cytosol to form phosphoenol pyruvate and other gluconeogenic intermediates. Propionyl-CoA is therefore an important precursor to glucose . Propionyl-CoA is the end product of odd-chain fatty acid metabolism, including most methylated fatty acids . The amino acids valine , isoleucine , and methionine are also substrates for propionyl-CoA metabolism. Propionyl-CoA carboxylase (PCC) is

120-737: The multimeric structure of PCC allows cooperative interactions between the constituent PCCβ monomers that can generate a more functional form of the holoenzyme. a. Carbamazepine (antiepileptic drug): significantly lowers enzyme levels in the liver b. E. coli chaperonin proteins groES and groEL: essential for folding and assembly of human PCC heteromeric subunits c. Bicarbonate: negative cooperativity d. Mg and MgATP: allosteric activation a. 6-Deoxyerythronolide B: decrease in PCC levels lead to increased production b. Glucokinase in pancreatic beta cells: precursor of beta-PCC shown to decrease KM and increase Vmax; activation (See Template:Leucine metabolism in humans – this diagram does not include

132-544: The pathway for β-leucine synthesis via leucine 2,3-aminomutase) Racemase Too Many Requests If you report this error to the Wikimedia System Administrators, please include the details below. Request from 172.68.168.150 via cp1114 cp1114, Varnish XID 922563126 Upstream caches: cp1114 int Error: 429, Too Many Requests at Thu, 28 Nov 2024 07:47:31 GMT Complementation (genetics) Too Many Requests If you report this error to

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144-465: The α subunit (PCCα) or β subunit (PCCβ) can cause propionic acidemia in humans. When different mutant skin fibroblast cell lines defective in PCCβ were fused in pairwise combinations, the β heteromultimeric protein formed as a result often exhibited a higher level of activity than would be expected based on the activities of the parental enzymes. This finding of intragenic complementation indicated that

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