Disease relevance of CYB5R3

• We analyzed the NADH-cytochrome b5 reductase gene of hereditary methemoglobinemia type I and type III, by using PCR-related techniques [1].
• A cDNA coding for human liver NADH-cytochrome b5 reductase (cytochrome b5 reductase, EC 1.6.2.2) was cloned from a human liver cDNA library constructed in phage lambda gt11 [2].
• The amino acid sequence of soluble NADH-cytochrome b5 reductase purified from normal human erythrocytes was determined as one approach to understand the hereditary disease of a deficiency of this enzyme [3].
• Mitf regulation of Dia1 controls melanoma proliferation and invasiveness [4].
• HPLC analyses of products from reduction catalyzed by XO or diaphorase of Clostridium with NADH showed the following trends for the rates of amine formation from 9-oxo-2,7-diNF > 2,7-diNF; 9-oxo-2-NF > 9-hydroxy-2-NF > 2-NF; 2,7-diNF > 2-NF; and 9-oxo-2,7-diNF > 9-oxo-2-NF [5].

Psychiatry related information on CYB5R3

• A distinct subpopulation of striatal aspiny neurons, containing the enzyme nicotinamide adenine dinucleotide phosphate diaphorase, is preserved in the caudate nucleus in Huntington's disease [6].
• In this patient, NADH cytochrome b5 reductase deficiency was observed in lymphocytes and platelets as well as in erythrocytes, but this was not associated with mental retardation [7].
• We used histo- and immunocytochemical labeling methods to study the nitrogen monoxide (NO; a.k.a. nitric oxide) synthase (NOS)-/NADPH diaphorase-containing neurons (NOSN) in three patients with MND and dementia (MND+D), two patients with MND without dementia, and 19 controls that included patients with Alzheimer and non-Alzheimer dementias [8].
• The onset of diaphorase expression in the spiral ganglion cells corresponds to a critical period of synaptogenesis for these sensorineural cells [9].
• Neurogenic erectile dysfunction: the course of nicotinamide adenine dinucleotide phosphate diaphorase-positive nerve fibers on the surface of the prostate [10].

High impact information on CYB5R3

• In the pyloric tissues from the control patients, intense diaphorase activity was present in the nerve fibers of the circular musculature, in the neurons and nerve bundles of the myenteric plexus, and in some nerve fibers of the longitudinal musculature [11].
• With these key residues as a guide, conclusive evidence is presented that the ferredoxin reductase structure is a prototype for the nicotinamide dinucleotide and FAD binding domains of the enzymes NADPH-cytochrome P450 reductase, NADPH-sulfite reductase, NADH-cytochrome b5 reductase, and NADH-nitrate reductase [12].
• Sperm diaphorase: genetic polymorphism of a sperm-specific enzyme in man [13].
• Low Mitf levels lead to down-regulation of Dia1, reorganization of the actin cytoskeleton, and increased ROCK-dependent invasiveness, whereas increased Mitf expression leads to decreased invasiveness [4].
• The ability of Dia1 to regulate the actin network is crucial for the localization of adherens junction components to the cell periphery [14].

Chemical compound and disease context of CYB5R3

• A novel point mutation in a 3' splice site of the NADH-cytochrome b5 reductase gene results in immunologically undetectable enzyme and impaired NADH-dependent ascorbate regeneration in cultured fibroblasts of a patient with type II hereditary methemoglobinemia [15].
• Nucleotide substitutions in the gene for NADH-cytochrome b5 reductase were identified in three independent probands of hereditary methemoglobinemia type I. Patients in Kagoshima and Okinawa in Japan were shown to possess the same base change, from guanine to adenine at codon 57, which results in amino acid substitution from Arg to Gln [16].
• Finally, fibroblasts from a patient with type II hereditary methemoglobinemia (deficient in NADH cytochrome b5 reductase) showed virtually no activity for hydroxylamine reduction, compared with normal fibroblasts [17].
• Vaccinia virus F13L protein with a conserved phospholipase catalytic motif induces colocalization of the B5R envelope glycoprotein in post-Golgi vesicles [18].
• An antibody (C'-B5R) raised to a 15-amino-acid peptide from the translated B5R ORF reacted with a 42-kDa protein (gp42) found in vaccinia virus-infected cells and cesium chloride-banded EEV but not INV [19].

Biological context of CYB5R3

• Exonic point mutations in NADH-cytochrome B5 reductase genes of homozygotes for hereditary methemoglobinemia, types I and III: putative mechanisms of tissue-dependent enzyme deficiency [1].
• Two forms of NADH-cytochrome b5 reductase (b5R), an erythrocyte-restricted soluble form, active in methemoglobin reduction, and a ubiquitous membrane-associated form involved in lipid metabolism, are produced from one gene [20].
• The nucleotide sequence was determined for the gene of NADH-cytochrome b5 reductase of a patient of type II hereditary methemoglobinemia found in Yokohama, Japan. An in-frame deletion of 3 base pairs corresponding to codon 298 (TTC) was identified in the patient [21].
• Identification of alternative first exons of NADH-cytochrome b5 reductase gene expressed ubiquitously in human cells [22].
• Complete amino acid sequence of NADH-cytochrome b5 reductase purified from human erythrocytes [23].

Anatomical context of CYB5R3

• The library was screened by using an affinity-purified rabbit antibody against NADH-cytochrome b5 reductase of human erythrocytes [2].
• Prenatal development of nicotinamide adenine dinucleotide phosphate-diaphorase activity in the human hippocampal formation [24].
• Using electrophoretic and immunologic methods, it was possible to detect diaphorase P in various fetal tissues (brain, liver, kidney, muscle), whereas was not found in adult tissues with the exception of the brain [25].
• Microsomes, peroxisomes, and outer mitochondrial membranes, all containing endogenous cytochrome b5, incorporated large amounts of the hemoprotein in such a way that it was reducible by an inherent NADH cytochrome b5 reductase [26].
• NADH-cytochrome b5 reductase is the predominant NADH-diaphorase found in the human neutrophil (Blood 62:152, 1983) [27].

Associations of CYB5R3 with chemical compounds

• The mutation in type I is a guanine-to-adenine substitution in codon 57 of exon 3 of the NADH-cytochrome b5 reductase gene, and the sense of this codon is changed from arginine to glutamine [1].
• Structural role of serine 127 in the NADH-binding site of human NADH-cytochrome b5 reductase [28].
• Role of cysteine residues in human NADH-cytochrome b5 reductase studied by site-directed mutagenesis. Cys-273 and Cys-283 are located close to the NADH-binding site but are not catalytically essential [29].
• Serine 127 of human NADH-cytochrome b5 reductase was replaced by proline and alanine by site-directed mutagenesis [28].
• From these results it was concluded that none of the Cys residues of the enzyme are essential in the catalytic reaction, but Cys-273 conserved among the enzymes homologous to NADH-cytochrome b5 reductase homologous to NADH-cytochrome b5 reductase plays role(s) in facilitating the reaction [29].

Physical interactions of CYB5R3

• The electrostatic potential of the surface near the flavin-protruding side (dimethylbenzene end of the flavin ring) of NADH-cytochrome b5 reductase was positive over a wide area while that of the surface near the heme-binding site of cytochrome b5 was negative [30].

Enzymatic interactions of CYB5R3

• The deletion of the N-terminal region up to Thr36 of the native reductase (Mr 35,000) produced a truncated form (Mr about 31,000) which had full diaphorase activity but lost the capacity to catalyze the ferredoxin-dependent reaction [31].
• The present study thus revealed that both dehydrogenase and diaphorase enzymes from the two Clostridium species catalyzed a hydride transfer to CL-20 and showed stereo-specificity for pro-R hydrogen of NAD(P)H [32].

Co-localisations of CYB5R3

• Nerve terminals positive for NADPH- diaphorase were colocalized with SM alpha-actin-positive cells in the sclera and choroid, whereas TH-positive nerve terminals colocalized with SM cells in the choroid [33].

Regulatory relationships of CYB5R3

• Furthermore, diaphorase activity could not be stimulated in permeabilized neutrophils from X-linked CGD patients and in differentiated gp91(phox)-targeted PLB-985 cells that lacked normal expression of gp91(phox), but was restored to these cells following transduction with retrovirus encoding gp91(phox) [34].
• The human dioxin-inducible NAD(P)H: quinone oxidoreductase cDNA-encoded protein expressed in COS-1 cells is identical to diaphorase 4 [35].

Other interactions of CYB5R3

• 1. This region contains a linkage group that maps to mouse chromosome 15, region E, and includes the SIS, ARSA, and DIA 1 genes [36].
• Finally, K562 alone, at cell concentrations corresponding to effector cell:target cell (EC:TC) ratios of 1:1 and 1:10, reduced cytochrome c, but this reduction was not inhibited by SOD, thus suggesting a diaphorase activity [37].
• Regional assignment of arylsulfatase A, mitochondrial aconitase and NADH-cytochrome b5 reductase by somatic cell hybridization [38].
• The purified fractions, designated 1, 2, 3 and 4, all showed diaphorase and ferredoxin-dependent cytochrome c reductase activity [39].
• The decline of cytochrome b5 seemed to be more rapid than the decline in the activities of glutamate-oxaloacetate transaminase and NADH-cytochrome b5 reductase whose apparent half-lives were 210 and 240 days, respectively [40].

Analytical, diagnostic and therapeutic context of CYB5R3

• Molecular cloning of cDNAs of human liver and placenta NADH-cytochrome b5 reductase [2].
• The organization and the complete nucleotide (nt) sequence of the b5R gene encoding human NADH-cytochrome b5 reductase (b5R; EC 1.6.2.2) have been determined by a combination of restriction mapping and nt sequence analysis of overlapping genomic DNA clones [41].
• Prenatal diagnosis of recessive congenital methaemoglobinaemia type II: novel mutation in the NADH-cytochrome b5 reductase gene leading to stop codon read-through [42].
• NADH-cytochrome-b5 reductase and the high affinity isozyme of cytochrome P-450 purified by d-b5 affinity chromatography are poorly retained on t-b5 columns [43].
• Diaphorase staining, anti-NO synthase (NOS) immunocytochemistry and the NO-indicator, DAF-2, show that cells throughout the optic anlage contain NOS and produce NO [44].

References