Hexose monophosphate shunt dehydrogenases

FMN was first identified as the coenzyme of an enzyme system that catalyzes the oxidation of the reduced nicotinamide coenzyme, NADPH (reduced NADP), to NADP (nicotinamide adenine dinucleotide phosphate). NADP is an essential coenzyme for glucose-6-phosphate dehydrogenase which catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconrc acid. This reaction initiates the metabolism of glucose by a pathway other than the TCA cycle (citric acid cycle). The alternative route is known as the phosphoglneonate oxidative pathway, or the hexose monophosphate shunt. The first step is ... 

Fig. 1. Integrated scheme showing the metabolic systems of regulation operating in eu-ryhaline Crustacea (after ref. 9). Broken lines indicate an inhibitory action of the effector and the heavy lines indicate activation. Notice the key role played by glutamic dehydrogenase as well as the controls exerted on the reactions utilizing reducing equivalents. The cAMP concentration is higher in concentrated medium than in dilute medium. The hormone responsible for this effect is not yet identified. HMPS, hexoses monophosphate shunt.

Understand the physiologic importance of the hexose monophosphate shunt and understand reactions catalyzed by glu-cose-6-phosphate and 6-phosphogluconate dehydrogenases, transaldolase, and transketolase discuss the importance of the hexose monophosphate shunt in red cell physiology. 

Figure 18.10 The hexose monophosphate shunt pathway. A, glucose-6-phosphate dehydrogenase B, 6-phosphogluconate dehydrogenase C, pentose-5-phosphate iso-merase D, pentose phosphate epimerase E, transaldolase F, transketolase G, phospho-hexoseisomerase. (Reproduced by permission from Williams JF. A critical examination of the evidence for the reactions of the pentose pathway in animal tissues. Trends Biochem Sri December 316, 1980.)...

Pyruvate dehydrogenase, especially in the adipose tissue, is stimulated by a high insulin/glucagon ratio. This leads to the production of acetyl-CoA, which may enter the Krebs cycle in the fed state. The more likely possibility is the biosynthesis of fatty acids from acetyl-CoA. The latter requires NADPH, and for this reason, the hexose monophosphate shunt is also activated. 

A total of 14 NADPH molecules are utilized to make each palmitate molecule. It comes from three sources the malic enzyme (see earlier) provides one NADPH molecule for every acetyl-CoA molecule generated from citrate. For palmitate, this accounts for eight NADPH molecules. The rest must be derived largely from the hexose monophosphate shunt (see Chapter 18). A minor source of NADPH is cytosolic isocitrate dehydrogenase (see Chapter 18). The synthesis of one palmitate molecule thus requires an equivalent of 7 + (3)14 = 49 ATP molecules. 

Glucose 6-phosphate dehydrogenase The enzyme that catalyzes the rate regulating step of the hexose monophosphate shunt, which produces NADPH required for inactivating oxygen radicals and thereby protects the RBC membrane from radical attack and rapture. 

A number of studies on the metabolism of 3FG and 4FG in Locusta miaratoria have been undertaken. Both 3FG and 4FG are toxic to locust with LD50 s of 4.8 mg/g and 0.6 mg/g respectively. In vitro studies showed that 3FG is metabolized in the fat body, via the NADP-linked aldose reductase, to 3-deoxy-3-fluoro-D-glucitol (3FGL). This metabolite was detected in the hemolymph of the insect and shown to be both a competitive inhibitor and a substrate for NAD-linked sorbitol dehydrogenase, thereby generating 3-deoxy-3-fluoro-D-fructose (3FF) (541. Subsequently, it was shown by in vivo radio-respirometric analysis of C02 and appropriate chase experiments, that 3FG metabolism irreversibly inhibits glycolysis and not the hexose monophosphate shunt or tricarboxylic acid cycle (55). In addition, the release of fluoride ion and H20 from D-[3- H]-3FG was also observed. Based on the mechanism of aldolase (55) and triosephosphate isomerase... 

Metabolism of the hexose monophosphate shunt in glucose-6-phosphate dehydrogenase deficiency and closely interrelated reactions. 

Fig. 1. Pathway of fatty acid synthesis from glucose in animal tissues. The key enzymes or enzyme systems involved are (1) pyruvate dehydrogenase, (2) pyruvate carboxylase, (3) citrate synthase, (4) citrate translocation system, (5) citrate cleavage enzyme, (6) acetyl-CoA carboxylase, (7) fatty acid synthetase, (8) 3-phosphoglyceraldehyde dehydrogenase, (9) malate dehydrogenase, (10) malic enzyme, (11) hexose monophosphate shunt.

Glucose-6-P and 6-phosphogluconate dehydrogenases [46-51] of the hexose monophosphate shunt (A, Fig. 2) and malic enzyme [50-55] of the malate transhydrogenation cycle (B, Fig. 2) appear to be regulated both by variations in tissue levels and by metabolite effectors. The details of the regulation of these pathways are beyond the scope of this chapter. 

All the enzymes of the hexose monophosphate shunt have been found in the supernatant fraction of the cell. The enzymes of the glucuronic pathway, with the exception of NADP-L-hexonate dehydrogenase and aldonolactonase, which are found in the supernatant fraction of the cell, have a complex intracellular distribution. All the enzymes involved in glucuronic acid-1-phosphate synthesis and in the conversion of glucuronic phosphate or glucuronic acid to L-xylose or ascorbic acid are associated with the endoplasmic reticulum. The enzymes involved in the conversion of L-xylose to D-xylose are found in mitochondria. Thus, the complete glucuronic pathway involves three different cell fractions. 

Indeed, concomitantly to the loss of enzyme activity, there is, as might be expected, a drop in ATP and other phosphorylated compounds. In addition to a loss of dehydrogenase and hexokinase, the concentration of NAD drops rapidly. It is again not known if this results from accelerated breakdown or from a reduced rate of biosynthesis. Those that postulate that the reduced NAD in red cells results from interference with its synthesis have proposed several mechanisms to explain the reduced rate of biosynthesis of NAD, including (1) a reduction in ribose-5-phos-phate resulting from the impaired activity of the hexose monophosphate shunt and(2) a decrease in the activity of the enzymes involved in the biosynthesis of the coenzymes. 

In alloxan-diabetic rats, the amount of glucose oxidized through the hexose monophosphate shunt is below normal, and the activities of at least two important enzymes of the shunt pathway, glucose-6-phos-phate and 6-phosphogluconate dehydrogenase, are much lower in alloxan-diabetic animals than in normal animals. 

Rossi et al., 1972). As described in figure 1, there is an increase in glucose metabolism via the dehydrogenases of the hexose monophosphate (HMP) shunt, as well as ein increase in the non-mitochondrial consiomption of (Rossi et al.,... 

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