Hexose monophosphate pathway

Normally, approximately 10% of glucose is catabolized through the hexose monophosphate pathway, but this fraction may be markedly increased when there is oxidative stress, as is the case when there is an infection or use of certain drugs. The principal function of the hexose monophosphate pathway is to reduce 2 moles of NADP to 

NADPH by oxidizing G6P. NAD PH is required for a variety of biosynthetic pathways, for the stability of catalase and the regeneration and preservation of the reduced form of glutathione. These processes are crucial in the cell to detoxify hydrogen peroxide and protect the cell from oxidative stress. Since the red cell has no other sources of NADPH, it heavily depends on the prime enzyme of this reaction, glucose 6-phosphate dehydrogenase (G6PD). 

The enzyme is a dimer (predominantly) or tetramer (pH dependent) in the active form composed of identical subunits, 515 amino acids long and about 59kDa. The three-dimensional structure of human G6PD has been elucidated. The monomer is built up by two domains, an N-terminal domain and a large p a domain with an antiparallel nine-stranded sheet. The interface between the two monomers is of crucial importance for proper activity of the enzyme and is located in this second domain. 

The gene coding for G6PD is located on the X-chromo-some (Xq28), spans 18 kb, and consists of 13 exons. Exon 1 is noncoding. The promoter shares many features common to other housekeeping genes.  

The clinical expression of the disease is heterogeneous and five different clinical syndromes can be recognized  

---

Fig. 3. Biosynthetic pathways for amino acids. HMP = hexose monophosphate pathway CAC = citric acid cycle P = phosphate PP = pyrophosphate ...

False. D-gluconolactone is produced directly from glucose via glucose oxidase. 6-phosphogluconolactone is an intermediate in the hexose monophosphate pathway. 

Defects in the Hexose Monophosphate Pathway and Glutathione Metabolism... 

Mature red blood cells do not have nuclei, mitochondria, or microsomes therefore red blood cell function is supported through the most primitive and universal pathway. Glucose, the main metabolic substrate of red blood cells, is metabolized via two major pathways the Embden-Meyerhof glycolytic pathway and the hex-ose monophosphate pathway (Fig. 1). Under normal circumstances, about 90% of the glucose entering the red blood cell is metabolized by the glycolytic pathway and 10% by the hexose monophosphate pathway. 

The most important product of the hexose monophosphate pathway is reduced nicotinamide-adenine dinucleotide phosphate (NADPH). Another important function of this pathway is to provide ribose for nucleic acid synthesis. In the red blood cell, NADPH is a major reducing agent and serves as a cofactor in the reduction of oxidized glutathione, thereby protecting the cell against oxidative attack. In the syndromes associated with dysfunction of the hexose monophosphate pathway and glutathione metabolism and synthesis, oxidative denaturation of hemoglobin is the major contributor to the hemolytic process. 

Deficiencies of enzymes involved in glycolysis, the hexose monophosphate pathway, the closely related glutathione metabolism and synthesis, and nucleotide metabolism have emerged as causes of hereditary nonspherocytic hemolytic anemias (Table 1) (F10, Fll, M27). Some enzyme deficiencies, such as diphospho-glycerate mutase deficiency, lactate dehydrogenase deficiency, and NADH cy-... 

Triose phosphate isomerase (TPI) catalyzes the interconversion of glyceralde-hyde-3-phosphate and dihydoxyacetone phosphate and has an important role in glycolysis, gluconeogenesis, fatty acid synthesis, and the hexose monophosphate pathway. Red blood cell TPI activity measured in vitro is approximately 1000 times that of Hx, the least active glycolytic enzyme. TPI is a dimer of identical subunits, each of molecular weight 27,000, and does not utilize cofactors or metal ions. Posttranslational modification of one or both subunits may occur by deamidination, resulting in multiple forms of the enzymes and creating a complex multibanded pattern on electrophoresis. 

Glutathione reductase (GR) catalyzes the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) using NADPH provided from the hexose monophosphate pathway. GR, a ubiquitous flavoenzyme, maintains a high value of two for the GSH/GSSG ratio in the red blood cells. l,3-Bis(2-chloroethyl)-nitrosourea (BCNU) selectively inhibits cellular GR. GR is composed of two identical subunits, each of molecular mass 50 kDa (S8). The three-dimensional structure and mechanism of catalysis have been established for human GR (K17). 

The hexose monophosphate pathway has several names just to confuse you. It s called the hexose monophosphate shunt or pathway (HMP shunt or pathway), or the pentose phosphate pathway, or the phospho-gluconate pathway (Fig. 15-1). The pathway in its full form is complicated and has complicated stoichiometry. Usually it s not necessary to remember all of it. The important points are that it makes NADPH for biosynthesis and riboses (C-5 sugars) for DNA and RNA synthesis. 

Under basal conditions 5% of brain glucose is metabolized via the pentose phosphate shunt (PPS), also termed the hexose monophosphate pathway [66], a pathway active in both neurons and astrocytes. The PPS has... 

The pentose phosphate pathway (PPP, also known as the hexose monophosphate pathway) is an oxidative metabolic pathway located in the cytoplasm, which, like glycolysis, starts from glucose 6-phosphate. It supplies two important precursors for anabolic pathways NADPH+H+, which is required for the biosynthesis of fatty acids and isopren-oids, for example (see p. 168), and ribose 5-phosphate, a precursor in nucleotide biosynthesis (see p. 188). 

The oxidative pentose phosphate pathway (phosphogluconate pathway, or hexose monophosphate pathway) brings about oxidation and decarboxylation at C-l of glucose 6-phosphate, reducing NADP+ to NADPH and producing pentose phosphates. 

Veech, R.L. (2003) A humble hexose monophosphate pathway metabolite regulates short- and long-term control of lipogenesis. Proc. Natl. Acad. Sci. USA 100, 5578-5580. 

Hexose monophosphate pathway shown as a component of the metabolic map (see Figure 8.2,... 

Reactions of the hexose monophosphate pathway. Enzymes numbered above are 1) glucose 6-phosphate dehydrogenase and 6-phosphogluconolactone hydrolase, 2) 6-phosphogluconate dehydrogenase,... 

Increased activity of the hexose monophosphate pathway (HMP) The increased availability of glucose 6-phosphate in the well-fed state, combined with the active use of NADPH in hepatic lipogenesis, stimulate the HMP (see Chapter 12, p. 143). This pathway typically accounts for five to ten percent of the glucose metabolized by the liver (see Figure 24.3, ). 

The G-6-PD is a large structure with many genetic variants perhaps more than any other human protein (59-62). It is an almost ubiquitous cytosolic enzyme which catalyzes the first step in the hexose monophosphate pathway (62). Its most essential function is to produce the NADPH required to maintain the concentration of reduced glutathione (GSH) in the face of oxidative stress. The GSH together with catalase and glutathione peroxidase represent the defence against hydrogen peroxide, and this is particularly true in red blood cells. 

Cytosol Glycolysis, glycogenesis and glycogenolysis, hexose monophosphate pathway, fatty acid synthesis, purine and pyrimidine catabolism, aminoacyl-tRNA synthetases... 

The results indicated a specific conversion of C-6 of D-glucose into C-5 of D-ribose, explicable by the hexose monophosphate pathway, and suggested conversion of C-l of 2-amino-2-deoxy-D-glucose into C-l of D-ribose, which could be explained by the conversion of 2-amino-2-deoxy-D-glucose into D-glucose, and the operation, in S. fradiae, of some version of the glucuronate pathway for the removal of C-6 of D-glucose. 

Gale, N.L. and Beck, J.V., 1967. Evidence for Calvin cycle and hexose monophosphate pathway in Thiobacillus ferrooxidans. J. Bacteriol., 94 1052—1060. 

Figure 21 -8 Major glycolytic pathways of the erythrocyte. Substrates are in uppercase type, and enzymes are in parentheses. EMP, The Embden-Meyerhof pathway HMP hexose monophosphate pathway or pentose shunt RLC, the Rapoport-Luebering cycle ADP, adenosine diphosphate ATP, adenosine triphosphate NAD, nicotinamide-adenine dinudeotide NADH, reduced nicotinamide-adenine dinucleotide NADP, nicotinamide-adenine dinucleotide phosphate NADPH, reduced nicotinamide-adenine dinucleotide phosphate.The step from ribulose-5-phosphate, which is shown as being catalyzed by transketolase and transaldolase, is an abbreviation of this portion of the HMR...

---