NADH: cytochrome b5 reductase

T17. Tomatsu, S., Kobayashi, Y., Fukumaki, Y., Yubisui, T., Orii, T., and Sakaki, Y., The organization and the complete nucleotide sequence of the human NADH-cytochrome b5 reductase gene. Gene 80,353-361 (1989). 

Microsomal NADPH-Cytochrome P-450 Reductase and NADH cytochrome b5 Reductase... 

MICROSOMAL NADPH-CYTOCHROME P-450 REDUCTASE AND NADH CYTOCHROME b5 REDUCTASE... 

If the mechanism of superoxide production in microsomes by NADPH-cytochrome P-450 reductase, NADH-cytochrome b5 reductase, and cytochrome P-450 is well documented, it cannot be said about microsomal hydroxyl radical production. There are numerous studies, which suggest the formation of hydroxyl radicals in various mitochondrial preparations and by isolated microsomal enzymes. It has been shown that the addition of iron complexes to microsomes stimulated the formation of hydroxyl radicals supposedly via the Fenton... 

Eight human brain tumors contained DT-diaphorase, NADH cytochrome b5 reductase and NADPH cytochrome P450 reductase as assessed by enzyme activity and WB (Rampling et al., 1994). 

In humans, a variety of HA derivatives that are obtained by bioactivation of arylamine drugs (i.e. A-hydroxylation) or of pro-drugs that contain the NH—OH function, and whose activation requires the reduction of the hydroxylamine nitrogen atom, have been shown to undergo enzymatic reduction by the cytochrome f)5/NADH cytochrome b5 reductase system. ... 

The endoplasmic reticulum is composed of a convoluted network of channels and so has a large surface area. Apart from cytochromes P-450, the endoplasmic reticulum has many enzymes and functions, besides the metabolism of foreign compounds. These include the synthesis of proteins and triglycerides and other aspects of lipid metabolism and fatty acid metabolism. Specific enzymes present on the endoplasmic reticulum include cholesterol esterase, azo reductase, glucuronosyl transferase, NADPH cytochromes P-450 reductase and NADH cytochrome b5 reductase and cytochrome b5. A FAD-containing monooxygenase is also found in the endoplasmic reticulum, and this is discussed later in this chapter. 

Tertiary amine oxides and hydroxy la mines are also reduced by cytochromes P-450. Hydroxylamines, as well as being reduced by cytochromes P-450, are also reduced by a flavoprotein, which is part of a system, which requires NADH and includes NADH cytochrome b5 reductase and cytochrome b5. Quinones, such as the anticancer drug adriamycin (doxorubicin) and menadione, can undergo one-electron reduction catalyzed by NADPH cytochrome P-450 reductase. The semiquinone product may be oxidized back to the quinone with the concomitant production of superoxide anion radical, giving rise to redox cycling and potential cytotoxicity. This underlies the cardiac toxicity of adriamycin (see chap. 6). 

NADH cytochrome b5 reductase and cytochrome bs. The carbanion or carbene intermediates may rearrange with loss of a halogen ion (chap. 7, Fig. 77). 

There are other components of the P-450 system, namely, NADPH cytochrome P-450 reductase, NADH cytochrome b5 reductase, and cytochrome b5. 

Hackett, C.S., Novoa, W.B., Ozols, J. Strittmatter, P. (1986). Identification of the essential cysteine residue of NADH-cytochrome b5 reductase. Journal of Biological Chemistry 261, 9854-7. 

Hyde, G.E. Campbell, W.H. (1990). High-level expression in Escherichia coli of the catalytically active flavin domain of corn leaf NADH-nitrate, reductase and its comparison to human NADH-cytochrome b5 reductase. Biochemical and Biophysical Research Communications 168, 1285-91. 

Shirabe, K., Yubisui, T., Nishino, T. Takeshita, M. (1991). Role of cysteine residues in human NADH-cytochrome b5 reductase studied by site-directed mutagenesis. Journal of Biological Chemistry 266, 7531-6. 

This reaction is catalyzed by a membrane-bound complex of three enzymes NADH-cytochrome b5 reductase, cytochrome b5 and a desaturase. The overall reaction is ... 

Several of the reductases mentioned here belong to the same structural family (the FNR family), and they are mechanistically related to each other (9). A two-electron reduction of the flavin by NAD(P)H in these enzymes typically involves the transient formation of an oxidized flavin-reduced pyridine nucleotide charge-transfer complex, which is followed by hydride transfer. After reduction, the flavin can transfer its electrons to different redox partners. With NADH cytochrome b5 reductase, this transfer occurs in separate single-electron transfer steps. With... 

Nicotinamide adenine dinudeotide (NADH)-cytochrome b5 reductase (EC 1.6.2.2 cytbSr) uses NADH generated in the reaction in the Embden-Meyerhof pathway by glycer-aldehyde 3-phosphate dehydrogenase, to reduce the 12kDa protein cytochrome b5. Cytochrome b5 in turn reduces methemoglobm to hemoglobin. 

NADH-cytochrome b5 reductase deficiency (OMIM 250800) is an autosomal recessive disorder, causing hereditary methemoglobinemia. There are three types. In type I, the enzyme is deficient only in erythrocytes. Patients are typically blue and/or gray and cyanotic, but not very sick. Type II is more severe, the enzyme being completely deficient, causing mental retardation and neurological impairment. In type III the enzyme is deficient in all blood cells. 

Borgese N, Pietrini G. Distribution of the integral membrane protein NADH-cytochrome b5 reductase in rat liver cells, studied with a quantitative radioim-munoblotting assay. Biochem J 1986 239 393-403. 

Percy MJ, Gillespie MJ, Savage G, Hughes AE, McMuUin MF, Lappin TR. Familial idiopathic methemoglobinemia revisited original cases reveal 2 novel mutations in NADH-cytochrome b5 reductase. Blood 2002 100 3447-9. 

Yubisui T, Miyata T, Iwanaga M, Tamura M, Takeshita M, Complete amino add sequence of NADH-cytochrome b5 reductase purified from human ery-tfuocytes. J Biochem (Tokyo) 1986 99 407-22. 

Hereditary methemoglobinemia is a rare condition first described in Europeans but later found in individuals of many racial backgrounds. Familial methemoglobinemia in an autosomal recessive mode of transmission is due to a deficiency in the enzyme NADH-cytochrome b5 reductase. Hb variants that stabilize the ferric iron state are associated with an autosomal dominant famUial methemoglobinemia. Methemoglobinemia is treated by the administration of ascorbic acid or methylene blue. 

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