Disease relevance of DPYS

• Human DHPase and DRPs showed a lower degree of aa sequence identity with Bacillus stearothermophilus hydantoinase (39-42%) and Caenorhabditis elegans unc-33 (32-34%) [1].
• Subsequently, the utility of this detection system was also demonstrated with recombinantly expressed hydantoinase and amidase in E. coli [2].
• L-Hyd shows a strong homology both in fold and in metal coordination in the active site to another dihydropyrimidinase from Thermus sp. (D-hydantoinase) and to a slightly lesser degree to ureases, dihydroorotase and phosphotriesterase [3].
• This report describes the crystal structure of D-hydantoinase from Burkholderia pickettii (HYD(Bp)) at a 2.7-A resolution [4].
• The complete amino acid sequence of the hydantoinase from Arthrobacter aurescens DSM 3745 has been derived by automated Edman degradation [5].

High impact information on DPYS

• By using an eel testicular culture system, DHP was shown to induce DNA replication in spermatogonia [6].
• A natural progestin in teleost fish 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) and its receptors were present in the testis at an early stage of spermatogenesis [6].
• Although 11-ketotestosterone, a known initiator of spermatogenesis, also stimulated DNA synthesis in spermatogonia, antibodies against DHP prevented DNA replication when added during the period in which meiosis was initiated [6].
• We conclude that DHP, a progestin, is an essential factor for the initiation of meiosis [6].
• Furthermore, Spo11 expression and synaptonemal complexes, specific features of the meiotic prophase, were detected in testicular fragments cultured with DHP in some germ cells that showed morphological characteristics of undifferentiated spermatogonia [6].

Chemical compound and disease context of DPYS

• Indeed, the data from dihydropyridine-based calcium antagonist (DHP) trails are consistent in that they could not protect against new-onset heart failure or progression of renal disease in patients with left-ventricular systolic dysfunction or overt proteinuria, respectively [7].
• A partial dihydropyrimidinase deficiency proved to be a novel pharmacogenetic disorder associated with severe 5FU toxicity [8].
• These prospective studies will provide further valuable information whether nifedipine may be a preferred DHP to achieve BP goals in hypertensive patients with systolic dysfunction or overt proteinuria [7].

Biological context of DPYS

• The human DHP gene spans >80 kb and consists of 10 exons [9].
• Dihydropyrimidinase (DHP) deficiency (MIM 222748) is characterized by dihydropyrimidinuria and is associated with a variable clinical phenotype [9].
• A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distribution [1].
• The pyd2-1 mutant, which lacked the 5,6-dihydropyrimidine amidohydrolase (DHPase) activity, was transformed with wild-type S. kluyveri genomic library [10].
• We recently showed genetic linkage of hypoPP to loci on chromosome 1q31-32, co-localized with the DHP-sensitive calcium channel CACNL1A3 [11].

Anatomical context of DPYS

• Exposure to DHP also resulted in increasedlhbmRNA levels toward final oocyte maturation [12].
• Quantitative image analysis of the fluorescence emitted by the protoplasts showed the existence of interactions between PAA- and DHP-binding sites [13].
• By using RT-PCR amplification, Western blot with antibodies directed against the alpha1D subunit, binding assays with specific agonists or antagonists, and inhibition with specific antisense oligonucleotides, we show that DHP receptors are expressed and functional in primary human monocytes [14].
• Hepatocytes that contain both dihydropyrimidinase and dihydroorotase completely hydrolyzed dexrazoxane to ADR-925 and released it into the extracellular medium [15].
• Treatment of postvitellogenic ovarian follicles with IGF-I and b-insulin increased concentration of maturation-inducing hormone (MIH), 17alpha,20beta-dihydroxy-4-pregnane-3-one (DHP) in the medium [16].

Associations of DPYS with chemical compounds

• Substrate inhibition, hysteresis, allosterism, and the lack of dihydropyrimidinase are pointed out as special problems in assaying enzymes of pyrimidine degradation [17].
• It is known that thymine and uracil increase markedly in DHPDase deficiency, and 5,6-dihydrothymine and 5,6-dihydrouracil increase in DHPase deficiency [18].
• The diagnosis of IEM of purine and pyrimidine such as deficiencies of hypoxanthine-guanine phosphoribosyl transferase, adenine phosphoribosyl transferase, dihydropyrimidine dehydrogenase, dihydropyrimidinase and beta-ureidopropionase are described [19].
• The S. kluyveri DHPase was capable of catalysing both dihydrouracil and dihydrothymine degradation, presumably by the same reaction mechanism as that described for mammalian DHPase [10].
• DHPase activity and Northern analysis demonstrated that PYD2 expression is inducible by dihydrouracil, though not by uracil [10].
• Data presented in this study demonstrate that alterations of uracil catabolism are not limited to DPD deficiency, and that inactivating mutations in DHP might impair uracil catabolism in cases of normal DPD activity [20].

Other interactions of DPYS

• Enzymes of the pyrimidine base catabolism, dihydrouracil dehydrogenase (EC 1.3.1.2), dihydropyrimidinase (EC 3.5.2.2), and beta-ureidopropionase (EC 3.5.1.6) were compared in the cytosolic extract of several normal and neoplastic human tissues [17].
• It has been suggested that D-amino acid production from DL-5-substituted hydantoin involves the action of a series of enzymes involved in pyrimidine degradation, namely amide-ring opening enzyme, dihydropyrimidinase, and N-carbamoylamide hydrolyzing enzyme, beta-ureidopropionase [21].

Analytical, diagnostic and therapeutic context of DPYS

• Dihydropyrimidinase, on the other hand, is highly active in all solid tumors studied but not in their normal counterparts; therefore, we suggest that dihydropyrimidinase can serve as a good marker of tumorigenicity as well as a target for cancer chemotherapy of human solid tumors [17].
• Applications of thin-layer chromatography, high-performance liquid chromatography, and conventional cation-exchange amino acid analysis lead to detection of various defects in pyrimidine degradation, including the recently described deficiencies of dihydropyrimidine dehydrogenase and dihydropyrimidinase [22].
• We exposed female tilapia to graded doses of estradiol or 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) in vitro, and of estradiol in vivo, and determined mRNA levels ofgnrhr1,gnrhr3,drd2,lhb, andfshbby real-time PCR [12].
• Crystallization and preliminary X-ray analysis of a hydantoinase from Arthrobacter aurescens DSM 3745 [23].
• BACKGROUND: We investigated whether direct hemoperfusion with an immobilized polymyxin B column (DHP with PMX) could reduce the blood level of neutrophil elastase [24].

References