Lecture 14 Prodrug, biotransformatiion, enzyme induction and inhibition
Enzyme inhibition
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Transcript of Enzyme inhibition
M.Prasad NaiduMSc Medical Biochemistry,
Ph.D.Research Scholar
Definition: Any substance that decreases the velocity of an enzyme catalysed reaction.
Types of Inhibition:1. Competitive inhibition2. Non competitive inhibition3. Allosteric inhibition4. Suicide inhibition
Malonate
Statins
Statins inhibit HMG CoA reductase
Folate reductaseFolic acid Dihydrofolate
O Dihydrofolate reductase
Tetra hydrofolate
Methotrexate analogue of FH2 inhibits DHFR enzyme. Used in treatment of cancers.
Sulfonamide
PABA analoguePABA required for folate production in bacteriaSulfonamide prevent bacterial folate synthesis & prevent growth of bacteria.
Ethanol:analogue of methanol, used for the
treatment of methanol intoxication.
CH3OH HCHO (formaldehyde)
AD
HCOOH (Formic acid)HCHO Causes retinal damage & blindnessHCOOH produces severe acidosis & death
CH3CH2OH CH3CHO CH3COOH
NAD NADH
CH3CHO Less toxic
Ethanol competes for alcohol dehydrogenase &
prevents methanol toxicity.
Non Competitive Inhibition (Irreversible Inhibition)1.Heavy metals (mercury, lead, silver etc) bind covalently to – SH groups in the active site of the enzyme. They bind irreversibly they are highly toxic
E – SH + Hg2+ ES --- Hg2++ H+
Eg: delta ALA Porphobilinogen ALA dehydratase – Lead
Proto porphyrin IX Heme Fe2+
Ferrochelatase - Lead
2. Cyto chrome C oxidase inhibited by cyanide poisoning
Allosteric Inhibition:- 1.In glycolysis
HexokinaseGlucose glucose-6phosphate
ATP ADPGlucose-6phosphate acts as allosteric inhibitor for
hexokinase
Phospho fructo kinase2.Fructose-6phosphate fructose-
1,6bisphosphate
ATP ADP
ATP is negative allosteric modulator for PFK1
3. In TCA cycle ICD
Isocitrate alpha ketoglutarate
NAD NADH CO2
ATP is negative allosteric modulator for ICD
CO2
4. Acetyl CoA Malanoyl CoAAcetyl CoA carboxylase
Palmitate
Palmitate acts as negative allosteric modulator for acetyl CoA caboxylase
Suicide inhibition
It is a type of irreversible inhibition.
Also known as mechanism based inactivation.
Here , the structural analogue is converted into a
more effective inhibitor with the help of the
enzyme to be inhibted.
The substrate like compound initially binds with the
enzyme and the first few steps of the pathway
are catalysed.
This new product irreversibly binds to the enzyme and inhibits further reactions.
Substrate analogue of Hypoxanthine1.Hypoxanthine
XO (xanthine oxidase)
xanthine
xanthine oxidase
Uric acid
Allopurinol xo
xoAlloxanthine Uric acid
xanthine oxidase inhibits
1. Allopurinol alloxanthine
2. 5fluorouracil is used in the treatment of cancer
5Fluorouracil 5fluoro-deoxyuridylate
dUMP TMPThymidylate synthase
1. Compartmentalization of Pathways2. Induction & Repression of Enzymes3. Degradation of Enzymes4. Covalent Regulation5. Allosteric Regulation6. Iso enzymes
1. Compartmentalization
Enzymes for fatty acid synthesis are present in cytosolEnzymes for oxidation of fatty acids are present in mitochondria.
2. Induction & Repression Induction is increased synthesis of enzymes at
gene level through hormones or other substances.
Eg: Insulin induces the synthesis of glucokinase /glycogen synthase.
Repression is decreased synthesis of enzymes at gene level.Eg: Ala synthase is repressed by heme.
3. Enzyme degradationThe regulatory /key enzymes are degraded if not needed and they are rapidly synthesized when required.
Half lives of enzymes vary from one another.
4.Covalent Regulation
1.Irriversible by hydrolysis of chemical bonds - proenzymes.eg: Inactive enzymes Active enzymes
Zymogen / Proenzyme
HCLPepsinogen Pepsin
2. Reversible by phosphorylation and dephospharylation of enzymes
eg: Glycogen phosphorylase ( a & b)
5. Allosteric Regulation