Download HMP SHUNT & URONIC ACID PATHWAY

HMP SHUNT [Hexose Monophosphate Pathway] /
PPP [Pentose Phosphate Pathway]
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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]
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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]
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HMP
Anabolic
pathway
that utilizes
the 6
carbons of
glucose to
generate 5
carbon
sugars and
reducing
equivalents
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Oxidative reactions
1.
•
•
•
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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
2.
Hydrolysis of 6-PGL to 6-P-Gluconate by 6-PGL
hydrolase or lactonase - irreversible
3.
Oxidative decarboxylation of 6-P-Gluconate
by 6-PGluconate dehydrogenase
Irreversible
2nd NADPH is produced
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•
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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
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Products of HMP Shunt
G6P
NADPH
Biosynthesis (fatty
acids, steroid
hormones)
Ribose 5-P
Nucleic acid
synthesis
(DNA, RNA)
6G-6-P→ 5G-6-P regenerated, 6 CO2 eliminated,12 NADPH
generated, 1 Glucose is completely oxidized
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Uses of NADPH
1.
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.
2.
Reduction of H2O2: ROS- damage DNA, proteins, unsaturated
lipids– reperfusion injuries, cancer, inflammatory diseases,
aging.
Several protective mechanisms:
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
a.
b.
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3.
CYP 450 or Cyt P-450: major pathway for hydroxylation of
xenobiotics
Supply of NADPH is critical for liver microsomal cyt P-450
4.
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
a.
NADPH OXIDASE deficiency- Chronic granulomatosis
b.
Oxygen independent system- pH changes in phagolysosomes
and lysosomal enzymes- destroy pathogens
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G6PD and NADPH in the RBC
Glucose
Oxidant Stress
Certain Drugs
Infections
Fava Beans
Glucose
Erythrocyte
G6P
2 ADP
G6P
Glucose 6-phosphate
dehydrogenase
Glycolytic
pathway 6-Phospho2 ATP
2 Lactate
gluconate
HMP
NADPH
+ H+
H2 O2
2 GSH
NADP
Glutathione
reductase
Glutathione
peroxidase
GS-SG
G6PD deficiency prevents
the production of NADPH
in the erythrocyte. Lack of
NADPH results in hemolysis.
2 H2 O
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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
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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)
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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
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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 Lgulonolactone 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.
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URONIC ACID PATHWAY
G-6-P
Phosphoglucomutase
G-1-P
+ UTP [UDPG Phosphorylase]
UDP- Glucose
enters Uronic acid pathway
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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
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