1. HMP SHUNT [Hexose Monophosphate Pathway] / PPP [Pentose Phosphate Pathway]
Principle pathway for oxidation of Glucose-Glycolysis & TCA
HMP-alternative pathway for oxidation of Glucose-not for Energy
Occours in cytosol
Provides: NADPH [reductive synthesis] & Pentoses [for NA synth]
Most common at the site of synthesis:
Liver [phospholipid, FA synth, Cholesterol], adipose tissue [FA synth], lactating mammary gland [FA synth], adrenal cortex [Cholesterol, steroid hormone synth], testes & other endocrine glands concerned with steroid synthesis and RBC
NADPH produced: required for – Reductive biosynthesis of FA, TG, cholesterol, steroids
[NADH – reduction in Catabolic pathways (NADH enters ETC→ ATP);
NADPH – reduction in Synthetic pathways]

2. HMP
Anabolic pathway that utilizes the 6 carbons of glucose to generate 5 carbon sugars and reducing equivalents

3. Oxidative reactions Dehydrogenation of G-6-P by G6PD:
Irreversible oxidation to 6-PGL- sp. coenzyme NADP+
1st NADPH is produced
HMP-primarily regulated at G6PD
NADPH-comp inhibitor of G6PD
Hydrolysis of 6-PGL to 6-P-Gluconate by 6-PGL hydrolase or lactonase - irreversible
Oxidative decarboxylation of 6-P-Gluconate
by 6-PGluconate dehydrogenase
Irreversible
2nd NADPH is produced

4. Non-oxidative reactions
Interconversion of 3-, 4-, 5- and 7-Carbon Sugars
Ribulose 5-P to be converted to ribose 5-P [for Nucleic acid synthesis]
Or to intermediates of Glycolysis : F-6-P and Glycerladehyde-3-P
Non-oxidative part - controlled by availability of intermediates
Only coenzyme required: TPP for Transketolase reaction

5. Products of HMP Shunt
6G-6-P→ 5G-6-P regenerated, 6 CO2 eliminated,12 NADPH generated, 1 Glucose is completely oxidized

6. Uses of NADPH Reductive biosynthesis:
NADPH is a high energy molecule and electron donor. It is required as a source of electrons for biosynthesis of FA, cholesterol, sterols, hormones, and bile salts.
Reduction of H2O2: ROS- damage DNA, proteins, unsaturated lipids– reperfusion injuries, cancer, inflammatory diseases, aging.
Several protective mechanisms:
a. Enzymes that catalyze Antioxidant reactions:
Glutathione peroxidase or GOD [ using reduced Glutathione or GSH which is active as antioxidant, present in most cells which can detoxify H2O2 ]
Glutathione reductase or GR [regenerates GSH from oxidized glutathione formed in above reaction] using NADPH as a source of electrons
Antioxidant chemicals:
Vit E, A, C, uric acid, bilirubin, ceruloplasmin etc

7. 3. CYP 450 or Cyt P-450: major pathway for hydroxylation of xenobiotics
Supply of NADPH is critical for liver microsomal cyt P-450
Phagocytosis of microorganisms esp bacteria, foreign particles etc by Neutrophils & Macrophages:
imp defense mechanism
Oxygen dependent system- MPO [myeloperoxidase system]-most potent, NADPH OXIDASE [needs NADPH] in WBC cell memb, converts O2 into Superoxide FR [Respiratory burst]→Superoxide is converted by SOD [superoxid dismutase] into H2O2 →lysosomal MPO converts it to hypochlorous acid HOCl·→ kills bacteria
NADPH OXIDASE deficiency- Chronic granulomatosis
b. Oxygen independent system- pH changes in phagolysosomes and lysosomal enzymes- destroy pathogens

8. G6PD and NADPH in the RBC

9. G-6-PD deficiency
Inherited disease-most common disease producing enzyme abnormality in humans- X-linked
Hemolytic anemia due to inability to detoxify oxidizing agent
400 different types of mutations [point mutations]
Shortened life span due to complications
Increased resistance to falciparum malaria in female carriers of mutation
↓activity of G6-PD→↓NADPH [HMP] →↓detoxification of FR & peroxides
RBC- most vulnerable as HMP is only means for NADPH production. (other tissues NADP-dependent malate dehydrogenase also]
Precipitating factors- Oxidant drugs[ A-antibiotics (sulfamethoxazole), A-antimalarial (primaquin),A-antipyritics (acetanilid), ingest Fava beans [favism], severe infection-free radical generation in macrophages diffuse to RBC-hemolysis

10. Regulatory Mechanisms
Enzymes G6PD and 6PGD catalyze irreversible steps of the HMP shunt.
[NADPH] inhibits these enzymes via feedback inhibition
[ATP]: a putative inhibitor of these steps
 [G-6P] increases flux through the HMP shunt (G-6P is a substrate)

11. TPP is coenzyme for Transketolase
Transketolase reaction is measured in RBC as index of Thiamine status.
Wernicke-Korsakoff syndrome: seen in alcoholics and persons with Thiamine deficiency is due to genetic defect in the enzyme Transketolase

12. Uronic acid Pathway of Glucose
Importance in humans:
Provides UDP-glucuronic acid for conjugation [conjugation of bilirubin, steroids etc] and synthesis of glycosaminoglycans.
In lower animals (not in primates- deficiency of enzyme L-gulonolactone oxidase), this pathway leads to synthesis of Vit C.
Essential Pentosuria: one of Garrod’s tetrad [alkaptonuria, albinism, pentosuria, cystinuria- inborn error of metabolism]:
*1 in 2500 births due to deficiency of xylitol dehydrogenase →
L-xylulose excreted in urine gives + benedict’s test-not harmful. *Diffentiated from DM by + Bials test [orcinol in HCL-Bial’s reagent] by pentose sugars.

13. URONIC ACID PATHWAY G-6-P G-1-P UDP- Glucose
Phosphoglucomutase
G-1-P
+ UTP [UDPG Phosphorylase]
UDP- Glucose
enters Uronic acid pathway

14. Aldose reductase- Glucose to Sorbitol [glucitol]:
Lens, retina, Schwann cell of peripheral nerves, kidney, placenta, RBC, cells of ovaries and seminal vesicles.
Sorbitol dehydrogenase- Sorbitol to Fructose
Glucoe to Sorbitol to Fructose: in seminal vesicles for sperm cell [fructose is preferred carbohydrate energy source]
Hyperglycemia: Uncontrolled DM-large amt Glucose enters Lens, Retina,Nerve, Kidney – with action of aldose reductase
→↑Sorbitol, cannot pass through cell memb, so trapped inside cell.
Sorbitol dehydrogenase is absent in Lens, retina, kidney and nerve cell →↑sorbitol accumulates →Osmotic effects →cell swelling and water retention:
cause of cataract formation, peripheral neuropathy, vascular problems leading to nephropathy and retinopathy