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  1. Δ-Pyrroline-5-carboxylate (P5C) is both the immediate precursor and the degradation product of proline and is found not only intracellularly but also circulating in plasma. P5C reductase (EC catalyzes the conversion of P5C to proline as the committed step in biosynthesis. Proline oxidase (no EC number assigned) catalyzes the degradation of proline to P5C. Other sources of P5C are ornithine and glutamate in reactions catalyzed by ornithine-δ-aminotransferase (OAT) (EC and P5C synthase (no EC number assigned), respectively. The P5C “outflow” is primarily to glutamate in a reaction catalyzed by P5C dehydrogenase (EC The interconversions of P5C and proline constitute a cycle for transferring reducing-oxidizing potential between cellular organelles and between tissues.

  2. Two inherited disorders in the degradative limb of the proline metabolic system result in hyperprolinemia. Type I hyperprolinemia (HPI) (MIM 239500) is caused by deficiency of proline oxidase, and type II hyperprolinemia (HPII) (MIM 239510) is due to a deficiency of P5C dehydrogenase; both are apparently inherited as autosomal recessive traits. Proline levels are elevated three- to fivefold in the former condition and ten- to fifteenfold in the latter. The distinguishing biochemical characteristics in HPII are high plasma P5C levels and urinary excretion of P5C.

  3. Although the metabolic derangements in the hyperprolinemias are consistent with normal adult life, there appears to be a causal relationship between HPII and neurologic manifestations in childhood. Attempts at therapy by nutritional manipulation have been ineffective because the interconversions of the precursors makes it impossible to lower P5C or proline to any significant degree.

  4. A newly recognized disorder apparently related to the synthetic limb of this metabolic system has been described in two sibs with mental retardation, cataracts, joint hyperlaxity, and skin hyperelasticity. The biochemical phenotype, which includes hypoprolinemia, hypocitrullinemia, hypoornithinemia, and hyperammonemia, is consistent with a deficiency of P5C synthase. No direct measurements of P5C synthase activity in tissues from these patients have been described.

  5. 4-Hydroxy-L-proline is not synthesized as the free imino acid. Rather, it is produced by hydroxylation of the third-position proline in the prevalent Gly-Pro-Pro tripeptide of the procollagen polypeptide chain. Free hydroxyproline is derived from endogenous collagen turnover and from breakdown of dietary collagen. The hydroxyproline degradation pathway resembles that of proline. Δ1-Pyrroline-3-hydroxy-5-carboxylate, the oxidation product of hydroxyproline, is dehydrogenated to 4-erythro-hydroxy-L-glutamate. Transamination with oxaloacetate results in 4-hydroxy-2-ketoglutarate, which is then cleaved to glyoxalate and pyruvate in an aldolase reaction. The enzymes catalyzing these reactions are distinct from those for the degradation of proline, with one exception: dehydrogenation of P5C and hydroxy-P5C is catalyzed by the same enzyme, P5C dehydrogenase.

  6. Hyperhydroxyprolinemia (MIM 237000) is an autosomal recessive trait resulting from a deficiency of hydroxyproline oxidase (no EC number assigned). This biochemical disturbance apparently has no clinical consequence. The metabolism of proline and collagen are normal.

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