The human ENOX2 gene is located on the long (q) arm of the X chromosome in humans, at region 2 band 6 sub band 1, from base pair 130,622,330 to 130,903,317 (build GRCh38.p7) (map). The gene is conserved in chimpanzee, Rhesus monkey, dog, mouse, rat, chicken, and zebrafish.
ENOX2 and related NOX proteins exhibit two distinct oscillating functions: the oxidation of NADH to NAD+ and a protein disulfide isomerase-like activity, unprecedented in the biochemical literature. Regarding NADH oxidation, the protein has a specific activity of 10-20µmol/min/mg of protein with a turnover number of 200-500. The oscillations are independent of temperature, with a period of 24 minutes, completing 60 cycles in a 24 hour day. The period of oscillation changes to 22 and 26 minutes in the cancer related (tNOX) and age-related (arNOX) forms respectively. This regular oscillation is attributed to the maintenance of biological clock
Numerous studies in the 1990's correlated NADH oxidase activity with cell growth. Conditions which stimulated cell growth also stimulated NADH oxidase activity and conditions that inhibited cell growth inhibited NADH oxidase activity. Further experimental evidence showed that the rate of cell enlargement oscillates within the 24 minute oscillation of ENOX function. Maximum cell growth rates correspond to the portion of the ENOX cycle involved in protein dulsulfide bridge formation. Theories suggest that ENOX is responsible for the breakup and formation of disulfide bonds in membrane proteins, thus maximum cell growth coincides with maximum protein disulfide interchange activity.
The cancer associated, drug responsive variant of ENOX, tNOX, arises as a splice variant and is found on the cell surface of human cancers. tNOX exhibits a periodicity of 22 minutes, compared to the native 24 minutes and can be inhibited by a number of anticancer drugs, without affecting the native ENOX. These properties of tNOX are being used to develop early detection and intervention mechanisms for human cancers.
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