Human cytochrome b5 reductase: structure, function, and potential applications

Abstract

Cytochrome b5 reductase is a flavoprotein that is produced as two different isoforms that have different localizations. The amphipathic microsomal isoform, found in all cell types with the exception of erythrocytes, consists of one hydrophobic membrane-anchoring domain and a larger hydrophilic flavin catalytic domain. The soluble cytochrome b5 reductase isoform, found in human erythrocytes, is a truncated protein that is encoded by an alternative transcript and consists of the larger domain only. 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. This protein has received much attention from researchers due to its involvement in many oxidation and reduction reactions, such as the reduction of methemoglobin to hemoglobin. Autosomal cytochrome b5 reductase gene deficiency manifests with the accumulation of oxidized Fe+3 and recessive congenital methemoglobinemia in humans. In this article, we provide a comprehensive overview of the structure and function of cytochrome b5 reductase from different eukaryotic sources and its potential use in the food industry, biosensor, and diagnostic areas.

NADH-Cytochrome b5 Reductase 3 Promotes Colonization and Metastasis Formation and Is a Prognostic Marker of Disease-Free and Overall Survival in Estrogen Receptor-Negative Breast Cancer*

“…CYB5R3 (NADH-cytochrome b5 reductase 3) is a membrane-bound enzyme found in the plasma membrane, mitochondrial outer membrane, endoplasmic reticulum, and other membranes of most cell types, while a soluble form is present in red cells (30). CYB5R3 participates in cholesterol biosynthesis, fatty acid homeostasis, and P-450-mediated hydroxylation of drugs and steroid hormones.…”

“…CYB5R3 participates in cholesterol biosynthesis, fatty acid homeostasis, and P-450-mediated hydroxylation of drugs and steroid hormones. Finally, CYB5R3 is involved in the trans-plasma membrane redox system that both protects against extracellular oxidants and prevents initiation of apoptosis by specific mechanisms (30,31). CYB5R3 is believed to play a role in cellular aging (31), and Siendones and colleagues (32) showed that CYB5R3 is involved in protection against cellular senescence as the primary human fibroblasts aged.…”

The Anticancer Agent Prodigiosin Is Not a Multidrug Resistance Protein Substrate

“…Significant progress has been made in uncovering the mechanisms of these anticancerous properties. The observed cellular effects include oxidative DNA damage (Elahian et al, 2012), the induction of mitochondria-mediated apoptosis, inhibition of phosphatases, and disruption of the pH gradient in various cellular compartments, and DNA intercalation, cell cycle arrest in late G1, and caspase activation Perez-Tomas et al, 2003;Francisco et al, 2007;Williamson et al, 2007).…”

Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy

“…However, the use of iNO can lead to excessive oxidative stress and toxic levels of MetHb (methemoglobinemia) 7,8 . To prevent clinically significant methemoglobinemia, infants receiving iNO have MetHb levels checked frequently; however, some centers are questioning the utility of this practice 8,9 .…”

“…A soluble form of these proteins in the erythrocytes is responsible for reducing MetHb back into functional hemoglobin. Several studies have demonstrated that methemoglobinemia is associated with genetic variations in both CYB5A and CYB5R3 , resulting in decreased enzyme activity 7,11–15 .…”