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  • Prolidase deficiency (PD) (MIM 170100) is a rare, autosomal recessive, panethnic disorder associated with massive imidodipeptiduria. Undegraded dipeptides are excreted in excess of 15 mmol/day. Affected children often present with severe skin ulcers, particularly on their hands and feet. Mild to severe mental retardation occurs in approximately 75 percent of cases. Additionally, PD individuals appear to be highly susceptible to infections, some of which have been fatal. There is considerable clinical heterogeneity and at least five asymptomatic PD individuals have been identified. Three of these had severely affected sibs and two were detected in newborn screening programs.

  • Prolidase (imidodipeptidase, peptidase D; EC is a ubiquitous cytosolic enzyme that catalyzes hydrolysis of dipeptides with a C-terminal proline or hydroxyproline. The enzyme is encoded by the peptidase D (PEPD) gene located at 19q12-q13.11. PEPD spans 130 kb and has 15 exons. The 2.1 to 2.2 kb mRNA is translated into a 493-amino acid protein with a predicted molecular weight of 54.3 kDa. Native prolidase is a homodimer. A second, less well-characterized enzyme able to catalyze hydrolysis of imidodipeptides is known as prolidase II. Its activity does not appear to compensate for deficiency of prolidase.

  • Prolidase is a metalloenzyme that is activated by Mn+2. The specificity and function of prolidase metal binding remains controversial. Recent reports indicate that Mn+2 incubation affects the Vmax but not the Km of prolidase and that Mn+2 also increases the thermostability of the enzyme. Some metals, such as Co+2, Mg+2 and Fe+2 stimulate enzyme activity to a lesser extent than Mn+2; others, such as Zn+2, Pb+2, Hg+2 and Cd+2, inhibit prolidase activity.

  • A structural model for prolidase has been proposed based on homology modeling with crystallized E. coli methionine aminopeptidase. There is a “pita-bread fold” in which five amino acid residues form two metal binding sites in each subunit. This predicted stoichiometric ratio is supported by atomic absorption spectroscopy on purified, activated human prolidase. The catalytic site of prolidase is predicted to contain an arginine and an acidic amino acid.

  • Mutation analysis in PD individuals has identified nine PEPD mutations. Most are CpG mutations and only one, G448R, has been found in multiple, unrelated individuals. Expression systems for testing the functional consequences of PEPD mutations use COS cells or NIH3T3 cells.

  • Proline is a nonessential amino acid. Its biosynthesis in human tissues occurs via the action of Δ-1-pyrroline-5-carboxylic acid reductase upon glutamic semialdehyde (see Disorders of Proline and Hydroxyproline Metabolism). Both glutamic acid and arginine (via ornithine) are precursors. Studies in cultured fibroblasts have shown, however, that these sources contribute to less than 10 percent of collagen-bound proline. This suggests a role for prolidase in recycling dipeptide-bound proline back to the free amino acid pool for utilization in protein biosynthesis. Prolidase substrates can entirely satisfy the growth requirements of cultured CHO cells auxotrophic for proline.

  • The ...

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