Figure 1

Biochemical pathways using bicarbonate produced by carbonic anhydrase VA (CAVA) and mapping of CAVA clinical mutations. (a) Dotted lines link CAVA-produced bicarbonate (orange) with the bicarbonate-dependent carboxylases (in italics and blue). Enzymes: CPS1, carbamoyl phosphate synthetase 1; PC, pyruvate carboxylase; PCC, propionyl CoA carboxylase; 3MCC, 3-methylcrotonyl CoA carboxylase. Metabolites: AS, argininosuccinate; 3MCCoA, 3-methylcrotonyl CoA; 3MGCoA, 3-methylglutaconyl CoA; AcCoA, acetyl CoA; αKG, α-ketoglutarate; OAA, oxaloacetate; SUC, succinyl CoA; Glu, glutamate; Gln, glutamine; Sac, saccharopine; Lys, lysine; ASP, aspartate; PEP, phosphoenolpyruvate; PYR, pyruvate; LAC, lactate. (b) Human wild-type CA5A gene representation with predicted mitochondrial targeting sequence (MTS) and predicted functional residues for zinc binding (blue), active site (green), and substrate binding (cyan). Clinical mutations are shown in pink. p.Ser233Pro, p.Lys185Lys, leading to the deletion of exon 4 and the deletion of exon 6, were published in ref. 8. (c) Mouse CAVA structure (Protein Data Bank code 1DMX) in the cartoon representation is gray. Functional residues are in the stick representation (C atoms are colored as in (b), and O atoms are red). Residues harboring the missense mutations studied here are shown as pink spheres, and the regions corresponding to exons 4 (residues 154–186) and 6 (residues 207–258) are colored in dark and light pink, respectively. Polymorphism p.Pro273Leu is represented as a yellow sphere and labeled. Polymorphisms p.Asn45Lys and p.Asn46Lys are not represented since the most N-terminal part of the protein is not included in the crystal structure. Zinc is represented as a small, dark gray sphere and labeled.