Disease relevance of PEPD

• Mutations at the PEPD locus cause prolidase deficiency (McKusick 170100), a rare autosomal recessive disorder characterized by iminodipeptiduria, skin ulcers, mental retardation, and recurrent infections [1].
• A homozygous missense mutation in PEPD encoding peptidase D causes prolidase deficiency associated with hyper-IgE syndrome [2].
• Characterization of a prolidase from Lactobacillus delbrueckii subsp. bulgaricus CNRZ 397 with an unusual regulation of biosynthesis [3].
• Data related to 467 French patients grafted from 1982 to 1995 for primary sensitive disease (PSD, 22%), primary refractory disease (PRD, 18%), first relapse (R1, 45%), or subsequent relapses (R2, 15%) were analyzed [4].
• In prolidase deficiency, the characteristic skin manifestations are inflammatory indurations and chronic leg ulcers [5].

Psychiatry related information on PEPD

• BACKGROUND: We describe a study of DSM-III-R Axis I diagnoses of lifetime comorbid nonsexual disorders in 60 males with paraphilias (PAs; N = 42) and nonparaphilic forms of sexual impulsivity-designated paraphilia-related disorders (PRD; N = 18) [6].
• Genetic deficiency of prolidase can lead to severe problems in child development, including mental retardation [7].

High impact information on PEPD

• Dynamin partners bind to the PRD and may either stimulate dynamin's GTPase activity or target dynamin to the plasma membrane [8].
• Free clathrin-coated vesicles were induced by a peptide-blocking endophilin's SH3 domain and by antibodies to the proline-rich domain (PRD) of synaptojanin [9].
• The same mutation caused a different degree of clinical phenotype of prolidase deficiency in this family, therefore factor(s) not related to the PEPD gene product also contribute to development of the clinical symptoms [10].
• Prolidase deficiency is an autosomal recessive disorder with highly variable symptoms, including mental retardation, skin lesions, and abnormalities of collagenous tissues [10].
• Transfection and expression analyses using the mutant prolidase cDNA revealed that a mutant protein translated from the abnormal mRNA had an Mr of 49,000 and was enzymatically inactive [10].

Chemical compound and disease context of PEPD

• Plasma prolidase activity was uncorrelated with six biochemical indexes to liver function (the aminotransferases, alkaline phosphatase, glutamyltransferase, total bilirubin, and serum albumin) or with the degree of cirrhotic fibrosis [11].
• These phenomena were accompanied by a significant elevation in prolidase activity and an increase in beta(1) integrin expression in stomach cancer, compared to control tissue [12].
• METHODS: We investigated the collagen content (hydroxyproline assay), expressions of beta(1) integrin, prolidase and gelatinases A and B (Western immunoblot) as well activities of prolidase (colorimetric assay) and gelatinases (zymography) in stomach cancer tissue (n = 10) [12].
• The activities of alanine aminopeptidase, leucine aminopeptidase, proline dipeptidase and prolyl dipeptidase in the mucosa of the small intestine. Investigations on normal children and patients with the malabsorption syndrome [13].
• The data suggest that the ability of netilmicin to form stable complexes with melanin may prevent its toxicity on prolidase activity and collagen biosynthesis [14].

Biological context of PEPD

• We used SSCP analysis on four overlapping cDNA fragments covering the entire coding region of the PEPD gene and detected abnormal SSCP bands for the fragment spanning all or part of exons 13-15 in three of the probands [1].
• One such syntenic arrangement includes the GPI-PEPD enzyme association on Xiphophorus linkage group IV and human chromosome 19 [15].
• Linkage between the loci for peptidase D and apolipoprotein CII on chromosome 19 [16].
• Human prolidase (PEPD, iminodipeptidase, EC 3.4.13.9) and related deficiencies were analyzed in terms of the nature and molecular biology of the enzyme and the molecular events seen in patients with this deficiency [17].
• As active prolidase was recovered in prolidase-deficient fibroblasts transfected with pEPD-W, this restoration of prolidase activity after transfection means that gene replacement therapy for individuals with this human disorder can be given due consideration [18].

Anatomical context of PEPD

• A panel of human-rodent somatic cell hybrids containing different regions of chromosome 19 has been used to obtain a regional localization for peptidase D. The results assign PEPD to the long arm of chromosome 19, in the region cen-q13.2[19]
• Cultured skin fibroblasts were obtained from two independent patients with abnormal prolidase [18].
• A single nucleotide change in the prolidase gene in fibroblasts from two patients with polypeptide positive prolidase deficiency. Expression of the mutant enzyme in NIH 3T3 cells [18].
• To assess the biochemical phenotypes of these and two previously identified PEPD mutations (G448R and delE452), we have designed a transient-expression system for prolidase in COS-1 cells [20].
• Comparison of the amino acid sequence predicted from the nucleotide sequence of the cDNA insert of the two clones with the partial amino acid sequence determined by Edman degradation of peptides derived from human erythrocyte prolidase established that both clones code for human prolidase [21].

Associations of PEPD with chemical compounds

• Close linkage to C3, SE, PEPD, APOC2, D19S7, D19S8 and D19S9 was excluded [22].
• The following loci could not be localized with full confidence: LDHA, NP, PEPD, ITP, and PGK [23].
• Prolidase (peptidase D) catalyzes hydrolysis of the di- and tripeptide with carboxyl-terminal proline and plays an important role in recycling proline in various cells and tissues [24].
• Thus, we conclude that prolidase activity responded to ECM metabolism (tissue remodeling) through signals mediated by the integrin receptor [25].
• Prolidase (EC 3.4.13.9) is a ubiquitously distributed imidodipeptidase that catalyzes the hydrolysis of C-terminal proline or hydroxyproline containing dipeptides [25].

Regulatory relationships of PEPD

• Prolidase activity in fibroblasts is regulated by interaction of extracellular matrix with cell surface integrin receptors [25].

Other interactions of PEPD

• The p53 transcription factor contains two separate tandem activation domains (AD1 and AD2), a proline-rich domain (PRD), and a C-terminal basic domain (BD) [26].
• A panel of human-rodent somatic cell hybrids containing translocation derivatives of human chromosome 19 has been used to assign the markers peptidase D, complement component 3, lysosomal mannosidase, lysosomal DNAase, chorionic gonadotropin beta-subunit, and a new polymorphic DNA sequence, to specific regions of chromosome 19 [27].
• Size exclusion chromatographies and SDS-PAGE analysis led to the conclusion that this prolidase was a homodimer [3].
• FAK-independent regulation of prolidase activity and collagen biosynthesis in MCF-7 cells [28].
• We have established that D19S7 is the most proximal of the available long-arm markers and confirmed that PEPD localizes to 19q, along with PVS, MSK19, and MSK37 [29].

Analytical, diagnostic and therapeutic context of PEPD

• Four PEPD mutations from five severely affected individuals were characterized by analysis of reverse-transcribed, PCR-amplified (RT-PCR) cDNA [1].
• The decrease in prolidase activity due to the treatment of confluent cells with DNR was not accompanied by any differences in the amount of the enzyme protein recovered from these cells as shown by western immunoblot analysis [30].
• The S-carboxymethylated fractions were enzymatically digested with pronase, carboxypeptidase A and B, leucine aminopeptidase and prolidase, and epsilon-(gamma-glutamyl)lysine isolated from digests by gel filtration and cation ion exchange chromatography [31].
• Reversible perfusion defects (RPD), alone or in combination, were seen in 17 patients (44.7%), persistent perfusion defects (PPD) in 31 (81.5%), and RPD and PRD combined existed in 14 patients (37%) [32].
• Kinetic study of paracetamol on prolidase activity in erythrocytes by capillary electrophoresis with Ru(bpy)(3) (2+) electrochemiluminescence detection [33].

References