Hexose monophosphate shunt pathway

• Hexose monophosphate shunt (HMS)


  Comprises both pentoses and hexoses, also referred to as the pentose phosphate pathway (PPP) or "Phosphate Shunt"
• Pentose phosphate pathway (PPP)

  A metabolic pathway, common to all living organisms, for the oxidation of glucose alternative to glycolysis
• The reactions of this pathway occur in the cytoplasm of almost all cells
• Functions of PPP


  • Regeneration of NADPH from NADP+
  • Provision or utilization of ribose
• The PPP has other functions, both anabolic and catabolic
• Pentoses involved in catabolism in yeasts, bacteria and humans

  • Ribose
  • Xylose
  • Arabinose
• In photosynthetic organisms the PPP contributes to carbon dioxide (CO2) fixation during the Calvin cycle
• Other intermediates provided by the PPP for biosynthetic processes

  • Erythrose 4-phosphate
  • Ribulose 5-phosphate
  • Sedoheptulose 7-phosphate
• Phosphogluconate pathway


  Branching from glycolysis, also called the hexose monophosphate shunt
• The phosphogluconate pathway oxidizes the monosaccharide but does not involve any direct production or consumption of ATP
• First evidence of the existence of the phosphogluconate pathway obtained by the studies of Otto Warburg


  1930s
• The pathway was fully elucidated thanks to the work of several researchers including Efraim Racker, Fritz Lipmann, Bernard Horecker and Frank Dickens


  1950s
• Oxidative phase of the pentose phosphate pathway

  Glucose 6-phosphate is converted to ribulose 5-phosphate with the concomitant formation of two molecules of NADPH and the release of C-1 of glucose as CO2
• Nonoxidative phase of the pentose phosphate pathway


  Several phosphorylated carbohydrates are produced, whose fate depends on the relative needs for NADPH, ribose 5-phosphate, and ATP of the cell
• Oxidative phase of the pentose phosphate pathway

  1. Oxidation of glucose 6-phosphate to 6-phosphoglucono-delta-lactone

  2. Hydrolysis of 6-phosphoglucono-delta-lactone to 6-phosphogluconate

  3. Oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate
• Glucose 6-phosphate dehydrogenase


  Catalyzes the oxidation of glucose 6-phosphate to 6-phosphoglucono-δ-lactone, yielding the first molecule of NADPH
• The reaction catalyzed by glucose 6-phosphate dehydrogenase is unique to the pathway and is an essentially irreversible committed step that is highly allosterically regulated
• Highest levels of G6PD are found in neutrophils and macrophages, where NADPH is used to produce superoxide radicals for defensive purposes
• Nonoxidative phase of the pentose phosphate pathway

  1. Isomerization of ribulose 5-phosphate to ribose 5-phosphate

  2. Epimerization of ribulose 5-phosphate to xylulose 5-phosphate

  3. Transketolase catalyzes the transfer of a two carbon unit from a ketose to an aldose

  4. Transaldolase catalyzes a reaction in the seventh step
• Transketolase


  The rate-limiting enzyme of the non-oxidative phase, catalyzes the transfer of a two carbon unit from a ketose to an aldose
• Three of the four products of the reactions catalyzed by transketolase, two molecules of glyceraldehyde 3-phosphate and one of fructose 6-phosphate, are also intermediates of glycolysis
• Transfer of a two carbon unit

  1. Ketose (donor substrate) - xylulose 5-phosphate, sedoheptulose 7-phosphate or fructose 6-phosphate

  2. Aldose (acceptor substrate) - ribose 5-phosphate, glyceraldehyde 3-phosphate or erythrose 4-phosphate
• Transketolase


  Enzyme that catalyzes the transfer of a two carbon unit from a ketose to an aldose
• Reactions catalyzed by Transketolase


  1. Ketose donor - xylulose 5-phosphate

  2. Aldose acceptor - ribose 5-phosphate

  3. Products - glyceraldehyde 3-phosphate, sedoheptulose 7-phosphate

  4. Ketose donor - xylulose 5-phosphate

  5. Aldose acceptor - erythrose 4-phosphate

  6. Products - glyceraldehyde 3-phosphate, fructose 6-phosphate
• Transaldolase


  Enzyme discovered in 1953 by Horecker and Smyrniotis in brewer's yeast, catalyzes the transfer of a three carbon unit from sedoheptulose 7-phosphate to glyceraldehyde 3-phosphate to form fructose 6-phosphate and erythrose 4-phosphate
• Oxidative phase of pentose phosphate pathway

  1. Glucose-6-phosphate dehydrogenase oxidizes glucose-6-phosphate to 6-phosphogluconolactone, reducing NADP+ to NADPH

  2. Gluconolactonase cleaves the internal ester bond, giving 6-phosphogluconate

  3. 6-Phosphogluconate dehydrogenase reduces another NADP+ and decarboxylates 6-phosphogluconate to ribulose-5-phosphate
• Sugar shuffle stage of pentose phosphate pathway

  1. Ribulose-5-phosphate epimerase converts two molecules to xylulose-5-phosphate, one to ribose-5-phosphate

  2. Transketolase transfers a C2 unit from xylulose-5-phosphate to ribose-5-phosphate, yielding glyceraldehyde-3-phosphate and sedoheptulose-7-phosphate

  3. Transaldolase transfers a C3 unit from sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate, yielding fructose-6-phosphate and erythrose-4-phosphate

  4. Transketolase transfers a C2 unit from xylulose-5-phosphate to erythrose-4-phosphate, yielding a second fructose-6-phosphate and glyceraldehyde-3-phosphate
• NADPH


  Coenzyme that differs from NADH by one phosphate group, enabling it to interact with a separate set of enzymes
• NADH/NAD+ ratio


  Mostly oxidized, helps speed up oxidative reactions in TCA cycle and glycolysis
• NADPH/NADP+ ratio


  Mostly reduced, promotes reductive reactions in biosynthesis
• Uses of NADPH


  • Synthesis of fatty acids and cholesterol
  • Fixation of ammonia by glutamate dehydrogenase
  • Oxidative metabolism of drugs and poisons by cytochrome p450 enzymes
  • Generation of nitric oxide and reactive oxygen species by phagocytes
  • Scavenging of reactive oxygen species
• Regulation of pentose phosphate pathway

  1. Glucose 6-phosphate can enter glycolysis or pentose phosphate pathway depending on cell's need for ATP, NADPH and ribose 5-phosphate

  2. Fate of glucose 6-phosphate depends on relative activities of phosphofructokinase 1 (glycolysis) and glucose 6-phosphate dehydrogenase (pentose phosphate pathway)

  3. Cell can regulate carbon flow through phosphogluconate pathway based on need for NADPH, ribose 5-phosphate and ATP
• Glucose 6-phosphate dehydrogenase


  Major control point of carbon flow through pentose phosphate pathway and NADPH synthesis
• Regulation of glucose 6-phosphate dehydrogenase activity


  1. High NADPH levels inhibit the enzyme, while NADP+ is required for catalytic activity and active conformation

  2. Binding of acyl-CoA intermediates leads to dissociation into inactive monomers

  3. Insulin upregulates expression of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase
• Glucose-6-P dehydrogenase deficiency leads to reduced NADPH levels, weakening erythrocytes and making them more susceptible to oxidation
• Glucose-6-P dehydrogenase deficiency is linked to increased susceptibility to malaria
• Glucose-6-P dehydrogenase


  The first enzyme in the hexose monophosphate shunt, is an important enzyme for healthy cells, especially in the circulatory system
• Defects or deficiency of glucose-6-P dehydrogenase

  Leads to reduced levels of NADPH
• NADPH


  An important reductive role is to maintain glutathione in a reduced state
• Reduced glutathione (GSH) is a tripeptide that contains cysteine