The Proline Metabolic Pathway

Pyrroline-5-carboxylate reductase 1 is a mitochondrial enzyme that catalyzes the final step of proline biosynthesis by reducing pyrroline-5-carboxylate (P5C) into L-proline via NADH oxidation. Deficiency in PYCR1 leads to a recessive progeroid syndrome characterized by cutis laxa, joint hypermobility, dysmorphic features, and developmental delay. Referred to as De Barsy syndrome, PYCR1-deficient patients suffer from a premature ageing disease which can be regarded as an extreme form of the clinical spectrum of ARCL2B with more pronounced progeroid appearance, cataract or corneal clouding, and profound intellectual disability.

Mutations in PYCR2 (MIM616406) encoding the closely related enzyme pyrroline-5-carboxylate reductase 2 cause a phenotype with microcephaly and hypomyelination, but without skin manifestations.

Mutations in ALDH18A1 (MIM138250), which encodes the mitochondrial enzyme pyrroline-5-carboxylate synthase (P5CS) responsible for the conversion of glutamic acid to P5C, have been found in the most severely affected ARCL3 individuals.

PYCR1/2 and the enzyme proline dehydrogenase (PRODH) catalyzing the reverse reaction are key components of the proline cycle, which shuttles redox equivalents in and out mitochondria. Furthermore, this pathway is tightly connected to the urea cycle via ornithine aminotransferase (OAT) and to the TCA cycle via glutamate dehydrogenase (GLDH). P5CS and its counterpart pyrroline-5-carboxylate dehydrogenase (P5CDH) can also be regarded as integral parts of this proline cycle, because transporters for both end products, proline and glutamate, are present in mitochondria.