NADH-cytochrome b5 reductase 3 (CYB5R3)
The protein contains 301 amino acids for an estimated molecular weight of 34235 Da.
Desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction. (updated: March 4, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is predicted to be membranous by TOPCONS.
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Biological Process
Blood circulation
Cholesterol biosynthetic process
L-ascorbic acid metabolic process
Neutrophil degranulation
Nitric oxide biosynthetic process
Small molecule metabolic process
Vitamin metabolic process
Water-soluble vitamin metabolic process
Xenobiotic metabolic process
The reference OMIM entry for this protein is 250800
Methemoglobinemia due to deficiency of methemoglobin reductase
Nadh-dependent methemoglobin reductase deficiency
Nadh-cytochrome b5 reductase deficiency
Methemoglobinemia, congenital, autosomal recessive methemoglobinemia, type i, included
Me
A number sign (#) is used with this entry because autosomal recessive methemoglobinemia due to deficiency of methemoglobin reductase is caused by mutation in the CYB5R3 gene (613213). See also autosomal recessive methemoglobinemia type IV (250790), which is caused by mutation in the cytochrome b5 gene (CYB5A; 613218). Type III has been withdrawn (see below and Nagai et al., 1993). Autosomal dominant methemoglobinemia, referred to as the 'M' type, is caused by variation in the hemoglobin A (HBA1; 141800) or the hemoglobin B (HBB; 141900) gene.
DESCRIPTION
Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (review by Percy and Lappin, 2008). There are 2 types of methemoglobin reductase deficiency. In type I, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type II, 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 II methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (Vives-Corrons et al., 1978; Kaplan et al., 1979).CLINICAL FEATURES
Gibson (1948) and Barcroft et al. (1945) correctly concluded that erythrocytes from affected individuals with methemoglobinemia were unable to reduce methemoglobin that is formed continuously at a normal rate under physiologic conditions. Gibson (1948) is credited with identifying this disorder as an enzymatic defect in a reductase (seeHISTORY
below). Increased circulating levels of methemoglobin, which is brown, give the skin a bluish color, which appears as cyanosis. In the normal state, about 1% of hemoglobin exists as methemoglobin; individuals become symptomatic when methemoglobin levels rise above 25% (Jaffe, 1986). Vascular collapse, coma, and death can occur when methemoglobin approaches 70% of total hemoglobin (review by Percy and Lappin, 2008). - Methemoglobinemia Type I Tanishima et al. (1985) reported 2 Japanese brothers, born of consanguineous parents, with hereditary methemoglobinemia due to cytochrome b5 reductase deficiency. Katsube et al. (1991) provided follow-up of this family. The brothers, who were 24 and 26 years old, had moderate cyanosis without any evidence of neurologic involvement. Initial laboratory studies (Tanishima et al., 1985) showed lack of CYB5R3 enzyme activity in erythrocytes, leukocytes, and platelets. However, enzyme activity was not deficient in nonhematopoietic cells. Thus, the cases did not belong to either the classic erythrocytic or the generalized type, and was tentatively designated 'type III.' A study of relatives showed intermediate enzyme activity, consistent with heterozygosity. Tanishima et al. (1985) concluded that diagnosis by tissues other than blood cells may be important. Katsube et al. (1991) identified a homozygous mutation in the CYB5R3 gene (L149P; 613213.0003) in these patients. Further biochemical studies of these patients by Nagai et al. (1993) revealed that they did have residual enzyme activity in white blood cells, indicating that they actually had type I methemoglobinemia. As this was the only family repo ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 250800 was added.
Feb. 25, 2016: Protein entry updated
Automatic update: model status changed
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed