Type II hyperprolinemia. Delta1-pyrroline-5-carboxylic acid dehydrogenase deficiency in cultured skin fibroblasts and circulating lymphocytes.

Abstract

A B S T R A C T Type II hyperprolinemia is an inherited abnormality in amino acid metabolism characterized by elevated plasma proline concentrations, iminoglycinuria. and the urinary excretion of A1-pyrroline compounds. To define the enzymologic defect of this biochemical disorder, we developed a specific, sensitive radioisotopic assay for the proline degradative enzyme A'-pyrroline-5-carboxylic acid dehydrogenase. Using this assay, we have shown an absence of A'-pyrroline-5-carboxylic acid delhydrogenase activity in the cultured fibroblasts from three patients with type II hyperprolinemia. \Ve confirmed this result on cultured cells by demonstrating a similar absence of Al-pyrroline-5-carboxylic acid dehydrogenase activity in extracts prepared from the peripheral leukocytes of these patients. Additionally, we found significantly decreased levels of A'-pyrroline-5-carboxylic acid dehlvdrogenase activity in the leukocyte extracts from five obligate heterozygotes for type II hyperprolinemia. We also demonstrated a reduction in leukocyte AL-pyrroline-5-carboxylic acid dehydrogenase activity in three successive generations of a family.A portion of this work was presented at

Clinical, biochemical and enzymatic studies in type I hyperprolinemia associated with chromosomal abnormality.

“…The mother was suspected as a heterozygote. Recently, Valle et al (1976) clarified the significantly decreased levels of 5PC dehydrogenase activity in the leukocytes extracts and the cultured skin fibroblasts from obligate heterozygotes for type II hyperprolinemia and that this disease is inherited in an autosomal recessive fashion. However, it is impossible to determine the heterozygote of type I defect from the enzyme analysis, since proline oxidase enzyme is not present in blood leukocytes or skin fibroblasts (Dowing et al 1976).…”

Genetic evidence for a common enzyme catalyzing the second step in the degradation of proline and hydroxyproline.

“…who have been previously described (9). Our methods of culturing, harvesting, and sonicating the fibroblasts have also been described in complete detail (9).…”

“…Whether this reaction is catalyzed by two distinct enzymes or a common enzyme is uncertain. Adams and Goldstone (7) reported biochemical evidence in factor of a common enzyme, whereas the two-enzyme hypothesis is supported by the fact that plasma hydroxyproline concentrations are only minimally elevated in patients with type II hyperprolinemia (HP2), an inherited deficiency of PC dehydrogenase activity (9).…”

The Effect of L-Proline on Two Recombinant AMPA Glutamate Receptors

“…Although HPI and HPII result in elevation of proline levels, there are differences in the magnitude of proline elevation as well as in the mutations that cause these disorders (Valle et al 1976;Phang et al 2001;Jacquet et al 2002).…”

“…Proline levels are elevated 10 -15 fold in severe HPII with plasma concentrations as high as 413-1883 μM (Phang et al 2001;Afenjar et al 2007). The increase in proline in HPII is accompanied by an increase in the concentration of P5C, a by-product of proline degradation (Valle et al 1976). HPII is due to a mutation or deletion in the ALDH4A1 gene which codes for the enzyme P5CDH.…”