NNT (gene)

NAD(P) transhydrogenase, mitochondrial is an is_associated_with::enzyme that in humans is encoded by the NNT is_associated_with::gene on chromosome 5.

The NNT gene contains 26 exons and encodes a is_associated_with::transhydrogenase protein that is ~109 kDa in is_associated_with::molecular weight and is involved in antioxidant defense in the is_associated_with::mitochondria. Two alternatively spliced variants, encoding the same protein, have been found for this gene.

Structure
Transhydrogenases including NNT can exist in an ‘open’ conformation, where substrates can bind and products can dissociate, in which the dihydronicotinamide and nicotinamide rings are held apart to block hydride transfer. It can exist in an ‘occluded’ conformation, where the substrates are moved into apposition to permit redox chemistry. The protein comprises three subunits (dI, dII and dIII), with the dII component spanning the inner mitochondrial membrane. X-ray crystallography structure of the protein shows that proton pumping is probably coupled to changes in the binding affinities of dIII for NADP(+) and NADPH. The first betaalphabetaalphabeta motif of dIII contains a Gly-X-Gly-X-X-Ala/Val fingerprint, whereas the nicotinamide ring of NADP(+) is located on a ridge where it can interact with NADH on the dI subunit.

Function
NAD(P) transhydrogenase, mitochondrial is an integral protein of the is_associated_with::inner mitochondrial membrane. The enzyme couples hydride transfer of reducing equivalent between is_associated_with::NAD(H) and is_associated_with::NADP(+) to is_associated_with::proton translocation across the is_associated_with::inner mitochondrial membrane. Under most physiological conditions, the enzyme uses energy from the mitochondrial proton gradient to produce high concentrations of NADPH. The resulting NADPH is used for biosynthesis as well as in reactions inside the mitochondria required to remove is_associated_with::reactive oxygen species such as to retain a reduced glutathione pool (high GSH/GSSG ratio). The enzyme may be inactivated by oxidative modifications.

Reaction catalyzed:
 * NADPH + NAD+ = NADP+ + NADH.

Clinical significance
NAD(P) transhydrogenase, mitochondrial abundance may be associated with human is_associated_with::heart failure. In failing hearts a partial loss of NAD(P) transhydrogenase, mitochondrial activities negatively impacts the NADPH-dependent enzyme activities in the mitochondria and the capacity of mitochondria to maintain is_associated_with::proton gradients, which may be associated with the decline in energy production and is_associated_with::oxidative stress defense that is observed in heart failure.

Mutations in the NNT gene have been associated to familial is_associated_with::glucocorticoid deficiency 1, a severe is_associated_with::autosomal recessive disorder in human characterized by insensitivity to is_associated_with::adrenocorticotropic hormone action on the is_associated_with::adrenal cortex and an inability of the adrenal cortex to produce is_associated_with::cortisol is_associated_with::Glucocorticoid deficiency 1 usually presents in neonatal to early childhood with episodes of hypoglycemia and other symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, convulsions, and shock. Diagnosis is confirmed with a low plasma cortisol measurement in the presence of an elevated is_associated_with::adrenocorticotropic hormone level, and normal is_associated_with::aldosterone and plasma is_associated_with::renin measurements.