NADP
NADP (Nicotinamide Adenine Dinucleotide Phosphate) exists in two forms:
NADP+ is the oxidized form and NADPH is the reduced form.
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Reduction of NADP to NADPH
NADPH synthesis: Cytoplasm
Malate shuttle
NADPH synthesis: Mitochondria
Nicotinamide Nucleotide Transhydrogenase
NNT
A significant contributor to mitochondrial NADPH is the proton-translocating transhydrogenase that catalyzes the reaction
In the presence of an electrochemical proton gradient, Δp, i.e., under physiological conditions, the reaction is strongly shifted towards NADPH formation and the rate of the reaction from left to right is enhanced 5- to 10-fold. The redox level of mitochondrial NADP is normally more than 95% reduced, about half of which is uncoupler sensitive [17]. Thus, the uncoupler-sensitive part is consistent with transhydrogenase-generated NADPH, even though contributions by other sources, e.g., the NADP-isocitrate dehydrogenase, cannot be excluded. As judged from a flux investigation of redox equivalents in E. coli under different conditions, transhydrogenase accounts for up to 45% of the NADPH flow, the remaining contributed mainly by the pentose phosphate pathway, NADP-isocitrate dehydrogenase and decarboxylating malate dehydrogenase (malic enzyme) [18]. In mitochondria, the contribution of NADPH by transhydrogenase may thus be assumed to be at least as high or higher. It should also be stressed that transhydrogenase, at the high NADPH/NADP+ redox ratio prevailing in mitochondria, has been proposed to be largely product inhibited [19], i.e., its maximal activity, approx. 30 nmol/min/mg mitochondrial protein, is only reached upon a consumption of the product NADPH at a rate exceeding that of the steady-state rate of transhydrogenase.
Mitochondrial NADPH, transhydrogenase and disease 2006
Yeast NADH kinase
A novel NADH kinase is the mitochondrial source of NADPH in Saccharomyces cerevisiae 1993
Not yet describen in humans.
Oxidation of NADPH to NADP
- Ribonucleotide Reductase (first step of DNA synthesis)
- Fatty acid synthesis:
- >C=O => >COOH catalyzed by (3R)-3-hydroxyacyl-[acyl-carrier-protein]:NADP+ oxidoreductase, EC 1.1.1.100 (Other names: 3-oxoacyl-[acyl-carrier-protein] reductase; NADPH-specific 3-oxoacyl-[acylcarrier protein]reductase; 3-oxoacyl-[ACP]reductase; 3-ketoacyl acyl carrier protein reductase; β-ketoacyl-acyl carrier protein reductase; β-ketoacyl thioester reductase; β-ketoacyl-ACP reductase;β-ketoacyl-[acyl-carrier protein](ACP) reductase;β-ketoacyl reductase;β-ketoacyl acyl carrier protein (ACP) reductase)
* C=C => C-C catalyzed by acyl-[acyl-carrier-protein]:NAD+ oxidoreductase, EC 1.3.1.9 (other names: enoyl-[acyl-carrier-protein] reductase (NADH2; enoyl-[acyl-carrier-protein] reductase (NADH); enoyl-[acyl carrier protein] reductase; NADH-specific enoyl-ACP reductase; NADH-enoyl acyl carrier protein reductase; enoyl-ACP reductase;)
- Cholesterol biosynthesis (mevalonate pathway):
- -CO-S-CoA => -COH catalyzed by ®-mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34 ; HMG-CoA reductase; HMGR) 2 NADPH
- GSSG reduction to GSH
- CYP450 activity
- Proline synthesis
- Cyclooxygenase 1 and 2
- NO synthase 1, 2 and 3
Environmental factors affecting NADPH/NADP ratio
- Decrease (more oxidized status)