1umk

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1umk, resolution 1.75Å ()
Ligands:
Activity: Cytochrome-b5 reductase, with EC number 1.6.2.2
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

The Structure of Human Erythrocyte NADH-cytochrome b5 Reductase

Publication Abstract from PubMed

Erythrocyte NADH-cytochrome b(5) reductase reduces methaemoglobin to functional haemoglobin. In order to examine the function of the enzyme, the structure of NADH-cytochrome b(5) reductase from human erythrocytes has been determined and refined by X-ray crystallography. At 1.75 A resolution, the root-mean-square deviations (r.m.s.d.) from standard bond lengths and angles are 0.006 A and 1.03 degrees , respectively. The molecular structure was compared with those of rat NADH-cytochrome b(5) reductase and corn nitrate reductase. The human reductase resembles the rat reductase in overall structure as well as in many side chains. Nevertheless, there is a large main-chain shift from the human reductase to the rat reductase or the corn reductase caused by a single-residue replacement from proline to threonine. A model of the complex between cytochrome b(5) and the human reductase has been built and compared with that of the haem-containing domain of the nitrate reductase molecule. The interaction between cytochrome b(5) and the human reductase differs from that of the nitrate reductase because of differences in the amino-acid sequences. The structures around 15 mutation sites of the human reductase have been examined for the influence of residue substitutions using the program ROTAMER. Five mutations in the FAD-binding domain seem to be related to cytochrome b(5).

Structure of human erythrocyte NADH-cytochrome b5 reductase., Bando S, Takano T, Yubisui T, Shirabe K, Takeshita M, Nakagawa A, Acta Crystallogr D Biol Crystallogr. 2004 Nov;60(Pt 11):1929-34. Epub 2004, Oct 20. PMID:15502298

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[NCB5R_HUMAN] Defects in CYB5R3 are the cause of methemoglobinemia CYB5R3-related (METHB-CYB5R3) [MIM:250800]. A form of methemoglobinemia, a hematologic disease characterized by the presence of excessive amounts of methemoglobin in blood cells, resulting in decreased oxygen carrying capacity of the blood, cyanosis and hypoxia. There are two types of methemoglobinemia CYB5R3-related. In type 1, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type 2, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes and all body tissues. Type 2 methemoglobinemia is associated with mental deficiency and other neurologic symptoms.[1][2][3][4][5][6][7][8][9][10][11]

Function

[NCB5R_HUMAN] Desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction.

About this Structure

1umk is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Bando S, Takano T, Yubisui T, Shirabe K, Takeshita M, Nakagawa A. Structure of human erythrocyte NADH-cytochrome b5 reductase. Acta Crystallogr D Biol Crystallogr. 2004 Nov;60(Pt 11):1929-34. Epub 2004, Oct 20. PMID:15502298 doi:10.1107/S0907444904020645
  1. Yubisui T, Shirabe K, Takeshita M, Kobayashi Y, Fukumaki Y, Sakaki Y, Takano T. Structural role of serine 127 in the NADH-binding site of human NADH-cytochrome b5 reductase. J Biol Chem. 1991 Jan 5;266(1):66-70. PMID:1898726
  2. Katsube T, Sakamoto N, Kobayashi Y, Seki R, Hirano M, Tanishima K, Tomoda A, Takazakura E, Yubisui T, Takeshita M, et al.. 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. Am J Hum Genet. 1991 Apr;48(4):799-808. PMID:1707593
  3. Shirabe K, Yubisui T, Borgese N, Tang CY, Hultquist DE, Takeshita M. Enzymatic instability of NADH-cytochrome b5 reductase as a cause of hereditary methemoglobinemia type I (red cell type). J Biol Chem. 1992 Oct 5;267(28):20416-21. PMID:1400360
  4. Shirabe K, Fujimoto Y, Yubisui T, Takeshita M. An in-frame deletion of codon 298 of the NADH-cytochrome b5 reductase gene results in hereditary methemoglobinemia type II (generalized type). A functional implication for the role of the COOH-terminal region of the enzyme. J Biol Chem. 1994 Feb 25;269(8):5952-7. PMID:8119939
  5. Vieira LM, Kaplan JC, Kahn A, Leroux A. Four new mutations in the NADH-cytochrome b5 reductase gene from patients with recessive congenital methemoglobinemia type II. Blood. 1995 Apr 15;85(8):2254-62. PMID:7718898
  6. Wu YS, Huang CH, Wan Y, Huang QJ, Zhu ZY. Identification of a novel point mutation (Leu72Pro) in the NADH-cytochrome b5 reductase gene of a patient with hereditary methaemoglobinaemia type I. Br J Haematol. 1998 Jul;102(2):575-7. PMID:9695975
  7. Higasa K, Manabe JI, Yubisui T, Sumimoto H, Pung-Amritt P, Tanphaichitr VS, Fukumaki Y. Molecular basis of hereditary methaemoglobinaemia, types I and II: two novel mutations in the NADH-cytochrome b5 reductase gene. Br J Haematol. 1998 Dec;103(4):922-30. PMID:9886302
  8. Wang Y, Wu YS, Zheng PZ, Yang WX, Fang GA, Tang YC, Xie F, Lan FH, Zhu ZY. A novel mutation in the NADH-cytochrome b5 reductase gene of a Chinese patient with recessive congenital methemoglobinemia. Blood. 2000 May 15;95(10):3250-5. PMID:10807796
  9. Huang C, Xie Y, Wang Y, Wu Y, Ye Y, Zhu Z. [Arginine-glutamine replacement at residue 57 of NADH-cytochrome b5 reductase in Chinese hereditary methemoglobinemia] Zhonghua Xue Ye Xue Za Zhi. 1997 Apr;18(4):200-3. PMID:15622768
  10. Percy MJ, Gillespie MJ, Savage G, Hughes AE, McMullin MF, Lappin TR. Familial idiopathic methemoglobinemia revisited: original cases reveal 2 novel mutations in NADH-cytochrome b5 reductase. Blood. 2002 Nov 15;100(10):3447-9. Epub 2002 Jul 5. PMID:12393396 doi:10.1182/blood-2002-05-1405
  11. Percy MJ, Crowley LJ, Davis CA, McMullin MF, Savage G, Hughes J, McMahon C, Quinn RJ, Smith O, Barber MJ, Lappin TR. Recessive congenital methaemoglobinaemia: functional characterization of the novel D239G mutation in the NADH-binding lobe of cytochrome b5 reductase. Br J Haematol. 2005 Jun;129(6):847-53. PMID:15953014 doi:10.1111/j.1365-2141.2005.05526.x

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