Propionyl-CoA carboxylase - A review

Abstract

Propionyl-CoA carboxylase (PCC) is the enzyme which catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA and is encoded by the genes PCCA and PCCB to form a hetero-dodecamer. Dysfunction of PCC leads to the inherited metabolic disorder propionic acidemia, which can result in an affected individual presenting with metabolic acidosis, hyperammonemia, lethargy, vomiting and sometimes coma and death if not treated. Individuals with propionic acidemia also have a number of long term complications resulting from the dysfunction of the PCC enzyme. Here we present an overview of the current knowledge about the structure and function of PCC. We review an updated list of human variants which are published and provide an overview of the disease.

Keywords: 3-hydroxypropionate; Methylcitrate; Propionic acidemia; Propionyl-CoA carboxylase.

Figure 1

A. Diagram of TCA cycle and Propionate pathways with toxic intermediate sources PDH: pyruvate dehydrogenase complex, CS: citrate synthase, ACO2: mitochondrial aconitase, IDH2/3: mitochondrial isocitrate dehydrogenase 2 and 3 (NAD/NADP), OGDHc: 2- oxoglutarate dehydrogenase complex, C-VOMIT: cholesterol, odd chain fatty acids, methionine, isoleucine, threonine, PCC: propionyl-CoA carboxylase, MUT: methylmalonyl-CoA mutase, MCEE: methylmalonyl-CoA epimerase, MMAA: Cobalamin A, MMAB: Cobalamin B, SS: succinate synthase (succinyl-CoA ligase), SDH: succinate dehydrogenase, FH: fumarase, MDH2: mitochondrial malate dehydrogenase 2. B. Schematic illustrating current knowledge about the metabolic intermediates of dysfunctional PCC and their impact on other pathways. UC: urea cycle, MC: methylcitrate, CPS1: carbamoyl phosphate synthase 1, OX PHOS: oxidative phosphorylation system, PDH: pyruvate dehydrogenase complex.

FIGURE 2

A. Schematic of PCCA variants which are also listed in Appendix 1 Regions of the protein are also delineated. The transcript used for exon-intronic boundaries was NM_000282.3 which is the longest known isoform. B: Schematic of PCCB variants, exons and introns as listed in Appendix 2. Intronic-exonic boundaries as defined by Rodriguez- Pombo [35]. Abbreviations: A: Alanine; R: arginine; N:asparagine; D: aspartic acid; C: cysteine; E: glutamic acid; Q: glutamine; G: glycine; H: histidine; I: isoleucine; L: leucine; K: lysine; M: methionine; F: phenylalanine; P: proline; T: threonine; Y: tyrosine; W: tryptophan; V: valine; X: frameshift or stop; BCCP: biotin-carboxyl carrier protein; BC: biotin carboxylase domain; BT: biotin transferase region