Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Prolidase deficiency”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2026

Establishment of human induced pluripotent stem cell lines and isogenic gene-corrected controls from three patients with prolidase deficiency.

Prolidase deficiency is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the PEPD gene. To date, close to 200 patients have been reported worldwide with a poorly understood pathomechanism. The PEPD gene encodes an enzyme that is involved in the final steps of collagen degradation. Urine amino acid analysis or specific dipeptide analysis can establish the biochemical diagnosis. In this study, we reprogrammed peripheral blood mononuclear cells (PBMCs) from three prolidase deficient patients into induced pluripotent stem cell (iPSC) lines and additionally generated isogenic controls using CRISPR-Cas9 genome editing. The pathogenic PEPD variants identified in our patients were NP_000276.2:p.? (NIHTVBi032-A), NP_000276.2:p.(Ile415Asn)/NP_000276.2:p.(Trp326Ter) (NIHTVBi033-A), and NP_000276.2:p.(Arg265Ter) (NIHTVBi034-A). These iPSC lines are valuable models to help investigate the pathomechanism of prolidase deficiency.

Humans↗
PubMed1987

Immunochemical studies of human prolidase with monoclonal and polyclonal antibodies: absence of the subunit of prolidase in erythrocytes from a patient with prolidase deficiency.

Prolidase was highly purified from human liver and erythrocytes. NaDodSO4/acrylamide gel electrophoresis revealed that these preparations contained a major protein with MW = 56,000. The mass of prolidase was estimated on gel filtration to be MW = 97,000, for both enzyme preparations. A monoclonal antibody was raised against the liver enzyme and a specific antiserum against the erythrocyte enzyme. The monoclonal antibody (EP-2) recognized prolidase from erythrocytes and liver, in equal proportions. The antiserum also recognized the enzyme from erythrocytes and liver. Immunoprecipitation studies with these antibodies suggested only a single species of prolidase in erythrocytes and liver. Using an immobilized monoclonal antibody (EP-2) as an immunoadsorbent, prolidase was partially purified from crude extracts, and the protein of the partially purified enzyme was identified by immunoblotting using antiserum. A protein band with a MW = 56,000 was demonstrated specifically when crude extracts from the liver and erythrocytes were examined using NaDodSO4/acrylamide gel electrophoresis. The subunit protein was absent in erythrocytes from a patient with prolidase deficiency. We propose that the absence of the subunit is one cause of the prolidase deficiency.

Antibodies, Monoclonal↗
PubMedDate not supplied

Topical treatment of skin ulcers in prolidase deficiency.

Prolidase deficiency is a hereditary enzyme deficiency characterized dermatologically by chronic recurrent ulcers and scarring due to increased skin fragility. It has been speculated that the enzyme deficiency causes a relative deficiency of proline in the wounds of these patients and negatively affects clinical healing. Two ulcers in a 17-year-old girl with established prolidase deficiency were treated for 12 weeks with ointments containing amino acids in an open study comparing the effects of 5% proline and a combination of 5% proline plus 5% glycine. Both ointments caused significant reduction of the ulcer size (p < 0.02), but the 5% proline-5% glycine mixture caused a more rapid reduction (0.01 < p < 0.02). The results confirm previous findings in this rare inborn error of metabolism.

Administration, Topical↗
PubMed1990

Structural organization of the gene for human prolidase (peptidase D) and demonstration of a partial gene deletion in a patient with prolidase deficiency.

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. By using human prolidase cDNA as a probe, a chromosomal gene related to prolidase was isolated from human gene libraries. The human prolidase gene is over 130 kilobases long and is split into 15 exons. All of the splice donor and acceptor sites conform to the GT/AG rule. The transcription initiation site was determined by nuclease S1 mapping and primer extension and was located 131 bases upstream from the initiation codon. A "CAAT" box-like sequence was present 67 bases upstream from the cap site, but there was no "TATA" box-like sequence. There were seven sets of sequences resembling the transcription factor Sp1 binding sites. Four were upstream from the cap site, and three were downstream. We also analyzed findings in patients with prolidase deficiency with respect to major gene re-arrangement. Several hundred base deletions, including the 14th exon, were identified. Knowledge of the gene structure of human prolidase will facilitate further studies on the expression and regulation of this gene and provide necessary information for analyses of mutations in patients with this deficiency.

Base Sequence↗
PubMed1996

Expression and molecular analysis of mutations in prolidase deficiency.

Prolidase (E.C.3.4.13.9) cleaves iminodipeptides. Prolidase deficiency (PD; McKusick 170100) is an autosomal recessive disorder with highly variable penetrance. We have identified two novel alleles in the prolidase gene (PEPD) by direct sequencing of PCR-amplified cDNA from a PD individual asymptomatic at age 11 years: a 551G-->A transition in exon 8 (R184Q) and a 833G-->A transition in exon 12 (G278D). 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. The enzyme was expressed as a fusion protein carrying an N-terminal tag, the HA1 epitope of influenza hemagglutinin, allowing its immunological discrimination from the endogenous enzyme with a monoclonal antibody. Expression of the R184Q mutation produced 7.4% of control enzymatic activity whereas the expression of the G278D, G448R, and delE452 mutations produced inactive enzymes. Western analysis of the R184Q, G278D, and G448R prolidases revealed stable immunoreactive material whereas the delE452 prolidase was not detectable. Pulse-chase metabolic labeling of cells followed by immunoprecipitation revealed that the delE452 mutant protein was synthesized but had an increased rate of degradation.

Alleles↗
PubMed1984

Prolidase and prolidase deficiency.

Prolidase deficiency seems to be a rather rare metabolic disorder. However, many new cases can be detected because screening is easy to perform and enzymatic confirmation allows the differentiation from other iminodipeptidurias . Clinical symptoms are briefly reviewed, while biological considerations and prolidase properties are exhaustively described. Methods for investigating urinary iminodipeptides are given with results. Moreover, several collagen modifications observed in this disorder led us to formulate a hypothesis for their mechanism. Genetic considerations and treatment attempts are discussed.

Amino Acid Metabolism, Inborn Errors↗
PubMed1988

Prolinase activity in prolidase-deficient fibroblasts.

The activity of prolinase (EC 3.4.13.8) was studied in cultured skin fibroblasts derived from three patients with deficient prolidase (EC 3.4.13.9). With pro-val as substrate and manganese in the reaction buffer, prolinase activity was higher in prolidase-deficient cells than in control cells (mean (SEM) 917 (67) nmol min-1 mg-1, n = 3, control mean (SEM) 294, (50), n = 11). The Michaelis constants were not different for the pro-val and progly substrates in control and prolidase deficient fibroblasts. However, the constants for Vmax rose for both substrates in deficient cells. These results demonstrate that prolinase activity increases in prolidase-deficient fibroblasts as also shown in the plasma of patients with prolidase deficiency. We suggest that in prolidase-deficient fibroblasts, this rise in prolinase activity constitutes an attempt to compensate for the prolidase deficiency by increasing the greatly reduced intracellular proline pool.

Adult↗
PubMed2005

Characterization of prolidase activity in erythrocytes from a patient with prolidase deficiency: comparison with prolidase I and II purified from normal human erythrocytes.

OBJECTIVES: The purpose of this study was to investigate the effect of various amino acids and their metabolites on the activities of prolidase I and II from human erythrocytes compared to those in a patient with prolidase deficiency. DESIGN AND METHODS: Prolidase I and II from human erythrocytes were purified by using column chromatography. Prolidase activity against various iminodipeptides was determined by spectrophotometry using Chinard's method. RESULTS: The activities of prolidase I and II against glycylproline and methionylproline were enhanced by glycine, L- and D-isoforms of alanine and serine and D-isoforms of valine, leucine and isoleucine. L-isoforms of branched amino acids inhibited the activity of prolidase I. On the other hand, the activity of prolidase II was enhanced by all of these L-branched amino acids. The patient's prolidase activity was also enhanced by all the L- and D-branched amino acids. CONCLUSION: The activities of prolidase I and II against various iminodipeptides were prominently enhanced by glycine, but the effect of L-valine differed between the two enzymes. Enzymatic properties of the patient's prolidase were essentially the same as those of prolidase II.

Amino Acids↗
PubMed2002

Therapeutic apheresis exchange in two patients with prolidase deficiency.

BACKGROUND: Prolidase deficiency is a rare genetic disorder for which a cure has not yet been found. OBJECTIVES: To assess the effectiveness of apheresis exchange as a new therapeutic approach. METHODS: Apheresis exchanges were repeated monthly for four consecutive months, in parallel, on two patients, replacing prolidase-deficient red blood cells with normal filtered cells. Prolidase activity and urinary dipeptides were determined at regular intervals. RESULTS: The constant presence of active prolidase inside cells allowed a continuous, although partial, degradation of imidodipeptides, with a concomitant improvement of skin ulceration. CONCLUSIONS: Apheresis exchange could be a reasonable way of obtaining a clinical improvement in these patients.

Adult↗
PubMedDate not supplied

[Effective therapy with a glycine-proline ointment in a patient with recurrent ulcers from prolidase deficiency].

INTRODUCTION: Prolidase deficiency is a rare disease. Lower leg recalcitrant ulcerations are the most characteristic symptoms. CASE REPORT: Woman diagnosed of prolidase deficiency with leg recalcitrant and infected ulcerations. Dermatology service solicits a proline and glycline containing ointment after failing other topical treatment and a skin grafting. After initiation of treatment, ulcerations improved partially. FORMULA DESCRIPTION: According to "Real Decreto 175/2001, de 23 de febrero", Pharmacy service draws up an elaboration guide and a patient information leaflet of a proline 5%-glycine 5% water emulsive ointment. DISCUSSION: Topical application of a glycine-proline ointment is an alternative for the treatment of recalcitrant ulcerations and it has resulted in variable response. In our patient it has been effective, with a partial improvement of leg ulcerations and a decrease in admissions due to over infection.

Administration, Topical↗
PubMed1996

Use of capillary zone electrophoresis for analysis of imidodipeptides in urine of prolidase-deficient patients.

Prolidase deficiency (PD) is characterized by massive urinary excretion of imidodipeptides X-Pro and X-Hyp. We report the applicability of capillary zone electrophoresis to urinary imidodipeptide determination. The protocol is fast, simple, reliable, only small amounts of sample are required and there is minimal sample preparation. Electropherograms of urine samples from control subjects and four patients with prolidase deficiency were compared. The presence of imidodipeptides normally absent in urine was evident in patients' urine. Further analysis of urine samples enabled identification of excreted imidodipeptides and the pattern of excretion appeared to be heterogeneous for different patients. This method appears to be useful for identification of imidodipeptides in biological samples, as an efficient aid in diagnosis of PD, and as a method for providing more information about this disease.

Dipeptidases↗
PubMed1997

Effect of different surfactants on the separation by micellar electrokinetic chromatography of a complex mixture of dipeptides in urine of prolidase-deficient patients.

Prolidase deficiency is a severe disorder characterized by massive excretion of metabolites with closely related structures. At present, micellar electrokinetic chromatography is the separation method which provides the highest selectivity of structurally similar solutes. However, the structure of a surfactant can greatly affect the selectivity of separation depending on factors such as the length of hydrophobic alkyl chain or the nature of the hydrophilic group. Here we investigated the effect of three non-ionic and four anionic detergents for obtaining the best separation conditions for resolving imidodipeptide mixtures. The effect on resolution of variables such as temperature, surfactant concentrations and organic solvents was also examined. The greatest resolution was obtained at the lowest temperature studied (10 degrees C) using 50 mM sodium borate, pH 9.3 containing 50 mM pentanesulfonate and 10% (v/v) methanol. Under these experimental conditions almost all excreted components were baseline separated and identified.

Dipeptidases↗
PubMed1983

In-vitro responses to ascorbate and manganese in fibroblasts from a patient with prolidase deficiency and iminodipeptiduria: cell growth, prolidase activity and collagen metabolism.

After successful ascorbate and manganese treatment of a female patient with prolidase deficiency and iminodipeptiduria, we attempted to explain the mechanism of action of these drugs in vitro, using them preferentially on skin fibroblasts. Since in vivo, ascorbate and manganese seemed to be responsible for both biochemical and clinical improvement, they were also expected to activate prolidase activity in vitro. Cell growth and prolidase activity were accordingly observed in fibroblast cultures supplemented with these compounds. It seemed that only ascorbate accounted for the successful in vivo response. To understand the mechanism involved, we studied collagen metabolism and found a decreased proline pool, a massive increase of rapidly degraded collagen and moderate enhancement of type III collagen and type I trimer in the patient's fibroblasts. We believe that ascorbate allowed the prolidase-deficient cells to maintain a normal collagen pool by increasing collagen synthesis. Both the massive increase in cell growth in response to ascorbate and the bad response as regards the quality of the collagen produced confirm the secondary nature of this mechanism. However, the relationship between accelerated collagen catabolism and prolidase deficiency remains unclear.

Adult↗
PubMed2005

Intracellular delivery of liposome-encapsulated prolidase in cultured fibroblasts from prolidase-deficient patients.

Prolidase is a cytosolic exopeptidase whose deficiency causes the development of a rare autosomal recessive disorder known as Prolidase Deficiency (PD). The main manifestations of PD are intractable ulcerations of the skin, recurrent infections and mental retardation. At this time only a hazardous and expensive chronic therapy based on blood transfusions is the suggested treatment for PD. The aim of this work was to investigate the capability of utilizing liposomes as enzyme carriers: these vesicular systems have been recently evaluated as protein carriers for their potential in terms of "in vivo" localization, drug release and for protein stabilization in biological fluids. Liposomes were prepared, with a 1:1 PC:Col molar ratio with or without DSPE-PEG, by a thin-film hydration. Ex-vivo experiments were performed, incubating prolidase loaded liposomes with cultured fibroblasts from PD patients and from controls, to determine the amount of active enzyme delivered to cells. Evaluation of liposomes toxicity on cultured skin fibroblasts showed that liposomes did not interfere with cellular growth. Results showed that all the active prolidase encapsulated in the liposomes was completely vehiculated inside fibroblasts after 6 days incubation. SEM analysis suggests that prolidase is vehiculated inside the cell through liposome endocytosis.

Cells, Cultured↗
PubMed1998

Prolidase deficiency associated with pathologic myopia.

Deficiency of prolidase, a key enzyme in proline metabolism, is extremely rare and is usually associated with skin lesions, recurrent infections, characteristic facies, mental retardation, and splenomegaly. These clinical features are largely due to inhibition of normal recycling of proline, which causes an alteration in the metabolism of collagen and other proline-rich proteins. The case of a 25-year-old with all the recognized characteristics of prolidase deficiency is reported. Pathologic myopia, which has not been hitherto described in association with prolidase deficiency, is added to the clinical spectrum of this rare disorder.

Adult↗
PubMed2006

Different effects of sulfur amino acids on prolidase and prolinase activity in normal and prolidase-deficient human erythrocytes.

BACKGROUND: Prolidase and prolinase activity is known to be enhanced significantly in some diseases. Recently, the effect of amino acids on prolidase and prolinase activity in normal and prolidase-deficient human erythrocytes was investigated. It was reported that both enzymes were enhanced by glycine and alanine in the presence of MnCl(2). METHODS: Erythrocytes were isolated from heparinized blood from normal human and a patient with prolidase deficiency. Effects of various sulfur amino acids on prolidase and prolinase activities against iminodipeptides in the presence of 1 or 0.1 mmol/l MnCl(2) were investigated. RESULTS: Prolinase activity against prolylglycine in normal and prolidase-deficient erythrocyte lysates was inhibited by L-methionine, NAc-L-methionine and D,L-methionine in a concentration-dependent manner, but D-methionine enhanced the activity in low concentrations (0-20 mmol/l). D,L-Homocysteine inhibited the activity more strongly than other sulfur amino acids tested in a concentration-dependent manner. On the other hand, prolidase activity against glycylproline was enhanced by L-methionine, D-methionine, D,L-methionine, D,L-homocysteine thiolactone and D,L-ethionine. The rates of enhancement by these sulfur amino acids were in the following order: D,L-ethionine>D,L-methionine, D-methionine, D,L-homocysteine thiolactone>L-methionine (10 mmol/l). CONCLUSION: The prolinase activity in normal and prolidase-deficient erythrocyte lysates was inhibited by L-methionine, D,L-ethionine and D,L-homocysteine. On the other hand, prolidase activity in their erythrocyte lysates was enhanced by D,L-ethionine, D-methionine and L-methionine. These results indicate the effects of these sulfur amino acids on prolidase and prolinase activities were different.

Amino Acids, Sulfur↗
PubMed2004

Effects of amino acids and its metabolites on prolidase activity against various iminodipeptides in erythrocytes from normal human and a patient with prolidase deficiency.

BACKGROUND: The characteristics of prolidase in erythrocytes from controls and patient with prolidase deficiency were investigated. METHODS: The erythrocytes were isolated from the heparinized blood of normal human and a patient with prolidase deficiency. Effects of various amino acids and their metabolites on prolidase activity against iminodipeptides in presence of 1 mmol/l MnCl(2) were investigated. RESULTS: Prolidase activity against glycylproline in erythrocytes from normal human was strongly enhanced by glycine, L-alanine, L-serine with MnCl(2), but the activity was strongly inhibited by L-valine, and L-leucine. However, the stereoisomers, D-leucine and D-valine enhanced the activity. The prolidase activity against methionylproline in erythrocytes from the patient with prolidase deficiency was also enhanced by glycine, L-alanine and L-serine. The activity was inhibited by l-leucine, but D-leucine and L-valine enhanced the activity against various iminodipeptides. CONCLUSION: Prolidase activity against glycylproline in normal human erythrocytes and against methionylproline from the prolidase-deficient patient was enhanced strongly by glycine, alanine and serine with MnCl(2). However, this activity was inhibited by L-leucine, but was enhanced by D-leucine.

Amino Acids↗
PubMed1988

In situ activation of human erythrocyte prolidase: potential for enzyme replacement therapy in prolidase deficiency.

Deficiency of prolidase is frequently associated with skin lesions and mental retardation. Biochemically, the condition is marked by iminodipeptiduria. We have investigated the feasibility of using donor erythrocytes to replace the deficient enzyme. Prolidase occurs in erythrocytes in an inactive form. If erythrocytes are incubated overnight at 37 degrees C in the presence of 1 mM MnCl2, the intracellular Mn++ concentration increases from 0.014 to 2.04 micrograms/ml. As a consequence, the activity of prolidase in hemolysates increases to 159 mumol glycyl-L-proline hydrolyzed/h/ml compared to 5 mumol/h/ml for hemolysates of cells incubated in the absence of Mn++. Hydrolysis of glycyl-L-proline by intact erythrocytes is reduced by the slow rate of iminodipeptide transport into the cell; however, intact cells hydrolyzed this substrate at a rate 10-20 times faster after preincubation with MnCl2. After exogenous MnCl2 is removed from the storage buffer, high levels of erythrocyte prolidase activity persist for at least 13 days. The kinetic parameters for intact activated erythrocyte-catalyzed hydrolysis of glycyl-L-proline have been estimated. These values predict that donor erythrocytes, activated with Mn++ before transfusion could play a significant role in the recovery of proline from dietary sources of iminodipeptides in patients with prolidase deficiency.

Dipeptidases↗