Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lack of prolidase I (PD I) leads to prolidase deficiency, a disease characterized by intractable skin lesions, recurrent respiratory infections, and mental retardation. The present study was undertaken to characterize and determine the physiologic roles of different prolidase isoenzymes. Two isoforms of prolidase were isolated from rat kidney. PD I showed higher activity against seryl-proline and alanyl-proline, whereas PD II was active especially against methionyl-proline. PD I was highly concentrated in the small intestine and kidney, whereas PD II was shown not to vary in the organs examined. Expression of PD I and PD II in the small intestine were maximal within 1 wk of birth, and then rapidly declined. The changes of prolidase in the kidney and heart were found to differ slightly. N-benzyloxycarbonyl-l-proline and captopril inhibited PD I dose-dependently, but showed no inhibition of PD II at low concentrations. NiCl2 inhibited PD II much more effectively than PD I. Our findings suggest that PD I functions by way of an intestinal peptide carrier, which may also be regulated by the uptake of various iminodipeptides. Similarly, age-related alterations of prolidase isoenzymes suggest that intestinal PD II also participates in absorption of proline and other amino acids early in life.
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PMID:Prolidase isoenzymes in the rat: their organ distribution, developmental change and specific inhibitors. 1751 39

l-Proline concentration is primarily related to the balance of enzymatic activities of proline dehydrogenase [proline oxidase (POX)] and Delta-1-pyrroline-5-carboxylate (P5C) reductase. As a result, P5C plays a pivotal role in maintaining the concentration of proline in body fluids and inborn errors of P5C metabolism lead to disturbance of proline metabolism. Several inborn errors of proline metabolism have been described. Hyperprolinemia type I (HPI) is a result of a deficiency in POX. The POX gene (PRODH) is located on chromosome 22 (22q11.2) and this region is deleted in velo-cardio-facial syndrome, a congenital malformation syndrome. In addition, this gene locus is related to susceptibility to schizophrenia. The other type of hyperprolinemia is HPII. It is caused by a deficiency in P5C dehydrogenase activity. Hypoprolinemia, on the other hand, is found in the recently described deficiency of P5C synthetase. This enzyme defect leads to hyperammonemia associated with hypoornithinemia, hypocitrullinemia, and hypoargininemia other than hypoprolinemia. Hyperhydroxyprolinemia is an autosomal recessive inheritance disorder caused by the deficiency of hydroxyproline oxidase. There are no symptoms and it is believed to be a benign metabolic disorder. The deficiency of ornithine aminotransferase causes transient hyperammonemia during early infancy due to deficiency of ornithine in the urea cycle. In later life, gyrate atrophy of the retina occurs due to hyperornithinemia, a paradoxical phenomenon. Finally, prolidase deficiency is a rare autosomal recessive hereditary disease. Prolidase catalyzes hydrolysis of dipeptide or oligopeptide with a C-terminal proline or hydroxyproline and its deficiency can cause mental retardation and severe skin ulcers.
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PMID:Inborn errors of proline metabolism. 1880 17

In this paper we provide a detailed biochemical and structural characterization of the active site of recombinant human prolidase, a dimeric metalloenzyme, whose misfunctioning causes a recessive connective tissue disorder (prolidase deficiency) characterized by severe skin lesions, mental retardation and respiratory tract infections. It is known that the protein can host two metal ions in the active site of each constituent monomer. We prove that two different kinds of metals (Mn and Zn) can be simultaneously present in the protein active sites with the protein partially maintaining its enzymatic activity. Structural information extracted from X-ray absorption spectroscopy measurements have been used to yield a full reconstruction of the atomic environment around each one of the two monomeric active sites. In particular, as for the metal ion occupation configuration of the recombinant human prolidase, we have found that one of the two active sites is occupied by two Zn ions and the second one by one Zn and one Mn ion. In both dinuclear units a histidine residue is bound to a Zn ion.
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PMID:Identifying the structure of the active sites of human recombinant prolidase. 1941 62

Prolidase is a metallopeptidase that is ubiquitous in nature and has been isolated from mammals, bacteria and archaea. Prolidase specifically hydrolyzes dipeptides with a prolyl residue in the carboxy terminus (NH(2)-X-/-Pro-COOH). Currently, the only solved structure of prolidase is from the hyperthermophilic archaeon Pyrococcus furiosus. This enzyme is of particular interest because it can be used in many biotechnological applications. Prolidase is able to degrade toxic organophosphorus (OP) compounds, namely, by cleaving the P-F and P-O bonds in the nerve agents, sarin and soman. Applications using prolidase to detoxify OP nerve agents include its incorporation into fire-fighting foams and as biosensors for OP compound detection. Prolidases are also employed in the cheese-ripening process to improve cheese taste and texture. In humans, prolidase deficiency (PD) is a rare autosomal recessive disorder that affects the connective tissue. Symptoms of PD include skin lesions, mental retardation and recurrent respiratory infections. Enzyme replacement therapies are currently being studied in an effort to optimize enzyme delivery and stability for this application. Previously, prolidase has been linked to collagen metabolism and more recently is being associated with melanoma. Increased prolidase activity in melanoma cell lines has lead investigators to create cancer prodrugs targeting this enzyme. Thus, there are many biotechnological applications using recombinant and native forms of prolidase and this review will describe the biochemical and structural properties of prolidases as well as discuss their most current applications.
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PMID:Biotechnological applications of recombinant microbial prolidases. 1942 54

Prolidase deficiency is characterized by chronic ulcerative dermatitis, mental retardation, and frequent infections. In the present study we examined the characteristics of rat brain prolidase isoenzymes. Prolidase isoenzymes (PD I and PD II) were isolated from the rat brain using DEAE cellulose column chromatography. PD I showed higher activity against seryl-proline and alanyl-proline, while PD II was particularly active against methionyl-proline. Prolidase activity in the whole brain and in the different brain regions showed higher activity against methionyl-proline and seryl-proline. PD II activity was highest in the hippocampus, followed by the cerebellum, cerebral cortex, caudatum, and the midbrain. The most rapid changes in the activities of PD I and PD II occurred perinatally, with a peak at three days before birth and a nadir at two days after birth, which then gradually increased until 21 days. N-benzyloxycarbonyl-l-proline inhibited PD I activity against various substrates in a dose-dependent manner. In contrast, there was no inhibition of PD II activity against methionyl-proline at low concentrations. In summary, these data suggest that maintenance of levels of proline, other amino acids and peptides containing proline in the rat brain is regulated by prolidase isoenzymes. The age-related alterations in PD I and PD II also may help to elucidate the fundation of prolidase isoenzymes in brain nervous system.
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PMID:Activity of prolidase isoenzymes in the rat brain: subcellular and regional distribution during development. 1978 60

Prolidase deficiency (PD) is a rare recessive disorder resulting from mutations in the prolidase gene (PEPD); only 17 causative mutant alleles had been so far characterized. Prolidase is a ubiquitous enzyme that hydrolyses dipeptides with C-terminal proline or hydroxyproline residues and indeed, lack of this enzyme activity causes massive urine excretion of undigested iminodipeptides. The clinical manifestations of PD are widely variable, and include intractable skin ulcers, unusual face, different degree of mental retardation, and recurrent infections. No definitive treatment is at present available.We report an 8-year girl with a typical PD facies, normal intelligence, and recurrent deep ulcerations complicated by infections. She was found to be compound heterozygous for two novel mutations in PEPD, c.1133delACG and c.1301delT, affecting the C-terminal end of the enzyme where the active site is located. Given her life-threatening course, she underwent allogeneic hematopoietic stem cell transplantation (HSCT) from her HLA-identical brother, confirmed heterozygous for the c.1133delACG allele. Successful engraftment was documented by full-donor chimerism. Posttransplant monitoring of erythrocyte prolidase activity showed that the child had converted to a heterozygous pattern. Reduction of excreted urine dipeptides, evaluated by capillary electrophoresis, supported the effectiveness of the treatment. Unfortunately the patient died on day +92 of invasive fungal infection.Despite the unfavorable outcome, we provide the first evidence that HSCT has the potential to reverse some of the biochemical features of PD patients. The indication to transplant must be balanced against the clinical manifestation of individual patients.
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PMID:Partial Rescue of Biochemical Parameters After Hematopoietic Stem Cell Transplantation in a Patient with Prolidase Deficiency Due to Two Novel PEPD Mutations. 2343 Aug 76

Prolidase gene (PEPD) encodes prolidase enzyme, which is responsible for hydrolysis of dipeptides containing proline or hydroxyproline at their C-terminal end. Mutations in PEPD gene cause, in human, prolidase deficiency (PD), a rare autosomal recessive disorder. PD patients show reduced or absent prolidase activity and a broad spectrum of phenotypic traits including various degrees of mental retardation. This is the first report correlating PD and brain damages using as a model system prolidase deficient mice, the so called dark-like (dal) mutant mice. We focused our attention on dal postnatal brain development, revealing a panel of different morphological defects in the cerebral and cerebellar cortices, such as undulations of the cerebral cortex, cell rarefaction, defects in cerebellar cortex lobulation, and blood vessels overgrowth. These anomalies might be ascribed to altered angiogenic process and loss of pial basement membrane integrity. Further studies will be directed to find a correlation between neuroarchitecture alterations and functional consequences.
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PMID:Brain morphological defects in prolidase deficient mice: first report. 2530 48

Prolidase deficiency (PD) is a rare autosomal recessive disorder that has symptoms such as skin ulcers, characteristic facies, mental retardation, skeletal deformities, hematological anomalies, splenomegaly, and chronic infections. Deficiency of prolidase leads to the increased excretion of proline in urine, which causes impaired collagen synthesis and delay in wound healing. This case reports a 40-year-old female who has had cutaneous ulcers since the age of 7 years. We also recognized borderline intellectual functioning as well as hematologic abnormalities and splenomegaly. We present this rare case to draw attention to consider prolidase deficiency in the differential diagnosis of leg ulcers.
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PMID:A case of prolidase deficiency accompanying leg ulcers. 2569 19

Prolidase deficiency has been related to mental retardation and oxidative stress. The study aimed to observe plasma prolidase activity (PPA), total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) in patients with Parkinson's disease (PD). 240 subjects with PD and 150 healthy volunteers were considered as cases and controls, respectively. PPA, TOS, TAS, and OSI were measured spectrophotometrically. PPA and TAS in cases were more significantly decreased than controls (P < 0.01), while TOS and OSI were significantly increased (P < 0.001). In cases, nonsignificant, positive correlation was observed between PPA and TOS and OSI while significant, negative correlation was observed between PPA and TAS (P = 0.047). PPA in cases was nonsignificantly decreased with increased duration of PD (P = 0.747) while TAS was significantly decreased (P < 0.001) and TOS and OSI were significantly increased (P < 0.001). It was observed that higher age groups had decreased PPA, and TAS and increased TOS and OSI compared to lower age groups in cases. In summary, patients with PD have decreased PPA and increased oxidative stress compared to healthy volunteers. PPA was associated with oxidative stress markers in patients with PD. Decreased PPA and TAS and increased TOS and OSI were associated with progression of disease and higher age.
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PMID:Plasma Prolidase Activity and Oxidative Stress in Patients with Parkinson's Disease. 2634 50

Prolidase deficiency is an autosomal recessive disorder, which is associated with chronic skin ulcers, a characteristic facial appearance, mental retardation, and recurrent infections. This study describes 4 patients with recurrent leg ulcerations and abnormal facies who were first clinically suspected of prolidase deficiency and then biochemically confirmed. Two siblings and 2 other patients were admitted to our clinic at different times, and they had some common features such as chronic leg and foot ulcers recalcitrant to treatment, consanguineous parents, facial dysmorphism, mental retardation, and widespread telangiectasias. Physical examination and detection of low prolidase level in blood finally led us to the diagnose of ulcers secondary to prolidase deficiency. Prolidase deficiency is a rare genodermatosis and must be considered in the differential diagnosis of recurrent leg and foot ulcers that develop at an early age.
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PMID:A Rare Cause of Lower Extremity Ulcers: Prolidase Deficiency. 2663 45


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