Hexose Monophosphate Shunt (HMP Shunt)

Learning objectives To explain HMP shunt To underline the significance of HMP shunt To compare the features of HMP shunt & glycolysis To describe the process (reactions) of HMP shunt To explain the regulation of HMP shunt

Hexose Monophosphate Shunt (HMP Shunt) Also knows as “Pentose Phosphate Pathway (PPP)” “Pentose Cycle” “Phosphogluconate Pathway”

Occurrence of HMP Shunt HMP shunt is active in Liver, lactating mammary glands, thyroid, adipose tissue, leukocytes, RBCs, testes and adrenal cortex HMP shunt (PPP) is less active in skeletal muscle & non-lactating mammary glands Site:- Cytosol

Biomedical Importance Alternate pathway for oxidation of Glucose, with no ATP production, but has two major functions; Provides NADPH, required for reductive syntheses and some other reactions Provides pentoses, required for Nucleic Acids and Nucleotide synthesis Deficiency of certain enzymes leads to hemolytic anemia. e.g. G6P Dase (G-6-P dehydrogenase )

Comparison of HMP Shunt & Glycolysis S.No. HMP Shunt Glycolysis 1 Occurs in specialized tissues Occurs in all tissues 2 Site is Cytosol 3 Multi-cyclic Process Not a Multi-cyclic process 4 NADP used as Co-enzyme NAD used as Co-enzyme

Comparison of HMP Shunt & Glycolysis S.No. HMP Shunt Glycolysis 5 ATP required initially 6 ATPs not produced ATPs produced 7 CO2 is formed during HMP shunt No CO2 is formed during glycolysis 8 Pentoses are generated No pentose is generated 9 Only monophosphate intermediates Diphosphate intermediates are also involved

Overall Reaction 3 Glc – 6 – P 6NADP+ 6NADPH + H+ 3 Glc 3 Pentoses 2 Glc–6–P + 3CO2 + Glyceraldehyde–3–P 6NADP+ 6NADPH + H+ 3 Glc 3CO2 3 Pentoses 2 Glc + 1 Triose Or 6 Glc 6CO2 6 Pentoses 5 Glc

Phases of HMP Shunt Two Phases 1. Oxidative Phase Dehydrogenation and decarboxylation of Glucose-6-P to form pentose phosphates. (Enzymes – Dehydrogenases) 2. Non-Oxidative Phase Conversion of pentose phosphates to Glucose-6-P through a series of reactions (Enzymes – Transaldolase and Transketolase)

Reactions of HMP Shunt

Reactions of HMP Shunt

Reactions of HMP Shunt (Contd.) Enediol Ribulose-5-P Reactions of HMP Shunt (Contd.) TPP Nucleotides & Nucleic acids

Oxidative stage of Pentose Phosphate Pathway

Non-oxidative reactions of PPP

Reactions of HMP Shunt (Contd.)

Regulation of HMP Shunt Rate limiting enzyme is G-6-Pdase & the other dehydrogenase NADPH / NADP ratio NADPH inhibits both dehydrogenases Activity of dehydrogenases decreases in Diabetes mellitus and Starvation

Regulation of HMP Shunt Insulin (fed state) induces the synthesis of key enzymes (G6Pdase & 6-P-Gluconate-DH) Activity of these enzymes also increases in lipogenesis (fatty acid & steroid synthesis) Thyroid hormones also lead to increased activity of the dehydrogenases  increased HMP Shunt

Functions of NADPH NADPH is required for Synthesis of fatty acids Synthesis of Cholesterol (steroids) Synthesis of Glutamate from -ketoglutarate Synthesis of Tyrosine from phenylalanine Synthesis of Gulonic acid from glucuronic acid (Uronic acid pathway) Synthesis of tetra-hydro-folate(FH4) Conversion of oxidized glutathione to reduced glutathione (G–S–S–G) (2G – SH)

Role of Glutathione H2O2 increases the rate of oxidation of hemoglobin to methemoglobin and damages the cell membrane  leading to hemolysis Glutathione degrades (detoxifies) the free radicals and hydroperoxides produced in oxygen rich environments like RBCs

Glutathione disulfide Role of Glutathione Glutathione (GSH) H2O2 2H2O Glutathione disulfide (GSSG) Glutathione Peroxidase GSSG NADPH + H+ NADP+ 2GSH Glutathione Reductase

G-6-Pdase Deficiency Oxidant drugs which may cause drug-induced hemolysis in G-6-Pdase deficient subjects include: Antimalarials (Primaquin & Pamaquin) Analgesics (Acetyl salicylic acid, Phenacetin) Sulfonamides Furadentin & furoxone & many others