Mammalian proline-P5C biosynthesis and catabolism

Mammalian proline metabolism interconverts L-glutamate, L-ornithine, delta-1-pyrroline-5-carboxylate (P5C), and L-proline in mitochondria. Bifunctional P5C synthase first phosphorylates and then reduces glutamate to glutamate 5-semialdehyde/P5C. Ornithine aminotransferase reversibly connects the same intermediate pool to ornithine, supporting either proline synthesis or arginine/ornithine degradation. Pyrroline-5-carboxylate reductases produce proline, whereas proline dehydrogenase and P5C dehydrogenase return proline carbon to glutamate. ALDH4A1 also provides a shared downstream oxidation step in trans-4-hydroxy-L-proline degradation.

This revision exposes each chemical transformation as its own part. ALDH18A1 therefore appears in two consecutive leaves because its kinase and reductase domains perform distinct reactions. PYCR1 and PYCR2 are representatives of one family-level terminal reduction role rather than duplicate steps. The shared PYCR location is conservatively mitochondrial: matrix localization is directly curated for PYCR1, whereas PYCR2 is curated only to mitochondrion. OAT is reversible and can route the shared P5C/glutamate-5-semialdehyde pool toward either proline or glutamate. GO:0010133, the former proline-to-glutamate catabolism term, is obsolete, so GO:0006562 is used. OAT and PRODH cofactors are retained explicitly as pyridoxal 5'-phosphate (the chemistry underlying GO:0030170) and FAD (the chemistry underlying GO:0071949), respectively. Bacterial ProB-ProA and fused PutA architectures require separate concrete modules. Disease and signaling consequences remain outside this reaction chain.