| CYB5R3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | CYB5R3 , B5R, DIA1, cytochrome b5 reductase 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 613213; MGI: 94893; GeneCards: CYB5R3; OMA:CYB5R3 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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NADH-cytochrome b5 reductase 3 is an enzyme that in humans is encoded by the CYB5R3 gene. [5] [6]
The CYB5R3 gene is located on the 22nd chromosome, with its specific location being 22q13.2. The gene contains 12 exons. [7] CYB5R3 encodes a 34.2 kDa protein that is composed of 301 amino acids; 63 peptides have been observed through mass spectrometry data. [8] [9]
The entire gene is about 31 kb in length. Exon 2 contains the junction of the membrane-binding domain and the catalytic domain of b5R, which shows that there are two forms of b5R: a soluble form and a membrane-bound form. The 5' portion of this gene does not have typical regulatory transcriptional elements, but has the sequence G-G-G-C-G-G a total of five times. The GC content of this 5' portion of the gene is 86%, much higher than the average GC of the entire gene, which is 55%. There is also an atypical polyadenylation signal in the 3'-untranslated region of the gene. [5]
The protein encoded by the CYB5R3 gene is cytochrome b5 reductase, a flavoprotein that is produced as two different isoforms with different localizations. There is an amphipathic microsomal isoform that is found in all cell types but red blood cells; this isoform has one hydrophobic membrane-anchoring domain and one catalytic domain that is hydrophilic. The other isoform, a soluble cytochrome b5 reductase isoform, is found in human erythrocytes. This protein is truncated, and encoded by an alternative transcript that produces only the larger, hydrophilic domain. [10] The protein contains 4 cysteine residues, Cys-203, -273, -283, and -297. Cys-283 is thought to be involved in NADH binding by chemical modification; in fact, both Cys-273 and Cys-283 are thought to be close to the NADH-binding site. [11] The NH2-terminal structure of the membrane-binding domain is CH3(CH2)12-CO-Gly-Ala-Gln-Leu-Ser-Thr-Leu-Gly-His-Met-Val-Leu-Phe-Pro-Val-Trp-Phe-Leu-Tyr-Ser-Leu-Leu-Met-Lys. [12]
Two forms of NADH-cytochrome b5 reductase are known, a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondria and other membranes) and a soluble form in erythrocytes. The membrane-bound form has both membrane-binding and catalytic domains. The soluble form has only the catalytic domain. This gene encodes both forms of the enzyme which arise from tissue-specific alternative transcripts that differ in the first exon. Mutations in this gene cause methemoglobinemias. [7]
Cytochrome b5 reductase is involved in the transfer of reducing equivalents from the physiological electron donor, NADH, via an FAD domain to the small molecules of cytochrome b5. It's also heavily involved in many oxidation and reduction reactions, such as the reduction of methemoglobin to hemoglobin. [10] Of the two forms of NADH-cytochrome b5 reductase, the membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. [7]
Mutations in the CYB5R3 gene cause methemoglobinemia types I and II. This is a rare autosomal recessive disease due to a deficiency of isoform of NADH-cytochrome b5 reductase. [13] Many mutations of this gene and the subsequent disease manifestation have been described. [14] The disease manifests as the accumulation of oxidized Fe+3 in humans. [10] Type I recessive congenital methemoglobinemia (RCM) is characterized by a deficiency of the soluble isoform and manifests as the cyanosis of skin and mucous membranes. [15] In type II, the defect affects both isoforms and thus affects more general tissues such as red blood cells, leukocytes, and all body tissues. This type is associated with mental deficiency and other neurologic symptoms, which may be because the cytochrome b5 system plays a crucial role in the desaturation of fatty acids in the body. [16] Recently, it was reported that abnormal lipid metabolism related with the desaturation of fatty acids is likely to be a secondary phenotype rather than a direct cause of the disease. The authors describe new insights on the aetiology of neurological disorders caused by CYB5R3d deficiency. [17] One patient was described as having a new class of this disorder, type III. This condition was characterized by a deficiency of NADH cytochrome b5 reductase in lymphocytes, platelets, and erythrocytes, but this was not associated with mental retardation. [18]
CYB5R3 is known to interact with CYB5A, ENO1, and SUMO2 among other proteins. [7]
Methemoglobinemia, or methaemoglobinaemia, is a condition of elevated methemoglobin in the blood. Symptoms may include headache, dizziness, shortness of breath, nausea, poor muscle coordination, and blue-colored skin (cyanosis). Complications may include seizures and heart arrhythmias.
Methemoglobin (British: methaemoglobin, shortened MetHb) (pronounced "met-hemoglobin") is a hemoglobin in the form of metalloprotein, in which the iron in the heme group is in the Fe3+ (ferric) state, not the Fe2+ (ferrous) of normal hemoglobin. Sometimes, it is also referred to as ferrihemoglobin. Methemoglobin cannot bind oxygen, which means it cannot carry oxygen to tissues. It is bluish chocolate-brown in color. In human blood a trace amount of methemoglobin is normally produced spontaneously, but when present in excess the blood becomes abnormally dark bluish brown. The NADH-dependent enzyme methemoglobin reductase (a type of diaphorase) is responsible for converting methemoglobin back to hemoglobin.
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Rieske proteins are iron–sulfur protein (ISP) components of cytochrome bc1 complexes and cytochrome b6f complexes and are responsible for electron transfer in some biological systems. John S. Rieske and co-workers first discovered the protein and in 1964 isolated an acetylated form of the bovine mitochondrial protein. In 1979, Trumpower's team isolated the "oxidation factor" from bovine mitochondria and showed it was a reconstitutively-active form of the Rieske iron-sulfur protein
It is a unique [2Fe-2S] cluster in that one of the two Fe atoms is coordinated by two histidine residues rather than two cysteine residues. They have since been found in plants, animals, and bacteria with widely ranging electron reduction potentials from -150 to +400 mV.
Cytochromes b5 are ubiquitous electron transport hemoproteins found in animals, plants, fungi and purple phototrophic bacteria. The microsomal and mitochondrial variants are membrane-bound, while bacterial and those from erythrocytes and other animal tissues are water-soluble. The family of cytochrome b5-like proteins includes hemoprotein domains covalently associated with other redox domains in flavocytochrome cytochrome b2, sulfite oxidase, plant and fungal nitrate reductases, and plant and fungal cytochrome b5/acyl lipid desaturase fusion proteins.
Cholesterol side-chain cleavage enzyme is commonly referred to as P450scc, where "scc" is an acronym for side-chain cleavage. P450scc is a mitochondrial enzyme that catalyzes conversion of cholesterol to pregnenolone. This is the first reaction in the process of steroidogenesis in all mammalian tissues that specialize in the production of various steroid hormones.
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Erythrocyte membrane protein band 4.2 is a protein that in humans is encoded by the EPB42 gene. It is part of the red blood cell cytoskeleton.
In enzymology, a NADPH—hemoprotein reductase is an enzyme that catalyzes the chemical reaction
Cytochrome b5, form A, is a human microsomal cytochrome b5.
Spectrin beta chain, erythrocyte is a protein that in humans is encoded by the SPTB gene.
Collagen alpha-4(IV) chain is a protein that in humans is encoded by the COL4A4 gene.
Cathepsin E is an enzyme that in humans is encoded by the CTSE gene. The enzyme is also known as slow-moving proteinase, erythrocyte membrane aspartic proteinase, SMP, EMAP, non-pepsin proteinase, cathepsin D-like acid proteinase, cathepsin E-like acid proteinase, cathepsin D-type proteinase) is an enzyme.
Cytochrome c1, heme protein, mitochondrial (CYC1), also known as UQCR4, MC3DN6, Complex III subunit 4, Cytochrome b-c1 complex subunit 4, or Ubiquinol-cytochrome-c reductase complex cytochrome c1 subunit is a protein that in humans is encoded by the CYC1 gene. CYC1 is a respiratory subunit of Ubiquinol Cytochrome c Reductase, which is located in the inner mitochondrial membrane and is part of the electron transport chain. Mutations in this gene may cause mitochondrial complex III deficiency, nuclear, type 6.
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NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1) is an enzyme that in humans is encoded by the NDUFS1 gene. The encoded protein, NDUFS1, is the largest subunit of complex I, located on the inner mitochondrial membrane, and is important for mitochondrial oxidative phosphorylation. Mutations in this gene are associated with complex I deficiency.
Ankyrin 1, also known as ANK-1, and erythrocyte ankyrin, is a protein that in humans is encoded by the ANK1 gene.
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