Cytochrome b5 reductase 3 (CYB5R3)

Cytochrome b5 reductase 3 is a flavoprotein enzyme encoded by the CYB5R3 gene, found on chromosome 22q13.2, and exists in two main isoforms—one membrane-bound (in all tissues except red blood cells) and one soluble (specific to erythrocytes)[1][2][3]. It catalyzes the NADH-dependent transfer of electrons via FAD to cytochrome b5, playing critical roles in redox metabolism. Its main functions include desaturation and elongation of fatty acids, cholesterol biosynthesis, and the reduction of methemoglobin to hemoglobin, which is crucial for oxygen delivery[1][2][3][4]. Deficiency of this enzyme, usually through genetic mutations, leads to types I and II congenital methemoglobinemia, manifesting as cyanosis and (in type II) neurological impairment due to defective fatty acid/cholesterol metabolism and myelin formation[1][2]. The enzyme also participates in drug metabolism and interacts pharmacologically with agents such as methylene blue and nitric oxide[2][3]. Genetic variation can have clinical significance, impacting disease risk such as breast cancer in select populations[2].

Other names

NADH-cytochrome b5 reductaseMethemoglobin reductase (inaccurate synonym)CYB5R3Erythrocyte cytochrome b5 reductase

Reduction of methemoglobin by electron transfer (methylene blue serves as artificial electron carrier when CYB5R3 is deficient); Modulation of enzyme activity through gene polymorphisms (affects drug and oxygen handling); NADH-dependent electron transfer to cytochrome b5 in drug metabolism