NADPH, production, regulation

Glucose 6-phosphate dehydrogenase, the first enzyme in the oxidative pentose phosphate pathway, is also regulated by this light-driven reduction mechanism, but in the opposite sense. During the day, when photosynthesis produces plenty of NADPH, this enzyme is not needed for NADPH production. Reduction of a critical disulfide bond by electrons from ferredoxin inactivates the enzyme. 

Regulation of NADPH Production Fatty Acid Synthase Respiratory Quotient Data from Human Studies... 

Larochelle, M.. Drouin, S.. Robert, F., and Turcotte, B. (2006) Oxidative stress-activated zinc cluster protein StbSp has dual activator/repressor fiinctions required for pentose phosphate pathway regulation and NADPH production. Molecular and Cellular Biology. 26. 6690-6701. 

A common way in which the rate of a particular metabolic reaction can be controlled is through the supply of substrate. In the case of animal fatty acid synthetase, this regulation has been examined with regard to NADPH. However, it appears that NADPH production is adjusted to cope with the altering demands of fatty acid synthesis rather than the other way around. In contrast, supply of malonyl-CoA by acetyl-CoA carboxylase activity (section 3.2.7(a)) is considered to be a major factor regulating overall fatty acid (and lipid) formation under many conditions. 

Additionally, the myeloperoxidase system even regulates the duration of the respiratory burst because neutrophils from patients with myeloperoxidase deficiency (see 8.3) generate more reactive oxidants than control cells. Also, when myeloperoxidase is inhibited with a specific antibody or a specific inhibitor such as salicylhydroxamic acid, the duration of the respiratory burst, but not the maximal rate of oxidant production, is extended. This indicates that a product of the myeloperoxidase system inhibits the NADPH oxidase and so self-regulates reactive oxidant production during inflammation. 

These observations were taken further by examining whether y-interferon treatment could up-regulate NADPH oxidase function in CGD neutrophils and monocytes. It was found that 12 out of 13 patients with autosomal recessive CGD had increased oxidase activity upon y-interferon exposure the only patient not responding was the one devoid of the b cytochrome. In X-linked CGD, 9 of 13 showed no improvement, whereas 3 showed some improvement and 1 had oxidase activity increased to near-normal levels. Patients with atypical X-linked CGD (i.e. low oxidase activity and some cytochrome b) appear to respond best to y-interferon treatment. Interferons-a and -ft are without affect. This enhancement of oxidase function (detected by NBT slide tests and O2 production) is due, at least in part, to increased levels of mRNA for the heavy chain of cytochrome b. In the absence of y-interferon treatment, monocyte-derived macrophages have extremely low or undetectable levels of mRNA for the cytochrome b heavy chain however, this is increased about fivefold (to about 5% of normal) after y-interferon treatment. 

By regulating the partitioning of electrons between NADP+ reduction and cyclic photophosphorylation, a plant adjusts the ratio of ATP to NADPH produced in the light-dependent reactions to match its needs for these products in the carbon-assimilation reactions and other biosynthetic processes. As we shall see in Chapter 20, the carbon-assimilation reactions require ATP and NADPH in the ratio 3 2. 

To understand why isocitrate dehydrogenase is so intensely regulated we must consider reactions beyond the TCA cycle, and indeed beyond the mitochondrion (fig. 13.15). Of the two compounds citrate and isocitrate, only citrate is transported across the barrier imposed by the mitochondrial membrane. Citrate that passes from the mitochondrion to the cytosol plays a major role in biosynthesis, both because of its immediate regulatory properties and because of the chain of covalent reactions it initiates. In the cytosol citrate undergoes a cleavage reaction in which acetyl-CoA is produced. The other cleavage product, oxaloacetate, can be utilized directly in various biosynthetic reactions or it can be converted to malate. The malate so formed can be returned to the mitochondrion, or it can be converted in the cytosol to pyruvate, which also results in the reduction of NADP+ to NADPH. The pyruvate is either utilized directly in biosynthetic processes, or like malate, can return to the mitochondrion. 

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