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Biochemistry Group 7
Hanif Amin
Khayeer Al-Farouq
Syaffiq Othman
Khirrol Nizam
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LIST CHEMICAL THAT INHIBIT PARTICULAR ENZYME IN GLYCOLYSIS
AND THEIR MECHANISM OF INHIBITION
By Hanif Amin D11B043
Khayeer Al-Farouq D11B040
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Glycolysis
• 1st series of reaction that breaks glucose apart to
liberate energy it holds
• Takes place in cytoplasm of cells. Also with absence of O2
• Involves 10 steps• Divided into 3 stages
1st phase - An energy investment
2nd phase – Cleavage into 2 molecules
3rd phase – Liberates energy
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Glycolysisdiagram
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Enzyme inhibition • Competitive enzyme inhibition – competitive
blocker at the active site
• Non-competitive enzyme inhibition – non-
competitive blocker causes conformational changes
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Chemicals Mechanisms of inhibition
2-Deoxyglucose -Inhibits phosphorylation of glucose by
hexokinase
Lonidamine -Inhibits glycolysis and mitochondrial respiration
-Inhibits HK; disassociating HK from
mitochondria
3-Bromopyruvate -Inhibits HK; acts as an alkylating agent
Imatinib -Inhibit Bcr-Abl tyrosine kinase; causes a
decrease in HK and G6PD activity
Oxythiamine -Suppresses PPP by inhibiting transketolase;
inhibits pyruvate dehydrogenase
Abbreviations: HK, hexokinase; G6PG, glucose-6-phosphate dehydrogenase;
PPP, pentose phosphate pathway.
List Of Chemical & Mechanism Of Inhibition
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2-Deoxyglucose
• Act as competitive inhibitor.
• Inhibition of glycolysis at the step ofphosphorylation of glucose by hexokinase.
• Its reduced avaibality of glucose for glycolysis.
• A clinical trial suggest that 2-DG at dosses upto 250mg/kg appears safe for use combinationwith radiation therapy.
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Lonidamine
• Inhibit aerobic glycolysis in cancer cell.
• Its suppress glycolysis in cancer cells, through inhibition of the mitochondrially bound hexokinase.
• In ehrlich ascites tumor cell showed that lonidamine inhibits glycolysis in a dose-dependent manner, lead to decrease in cellular ATP.
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3-Bromopyruvate
• Inhibitor of hexokinase and has been shown to abolish ATP propduction and cause severe depletion of cellular ATP.
• Exhibits potent cytotoxic activity against cancer cell with mitochondrial respiratory defects.
• Its cause rapid dephosphorylation that lead to massive cell death.
• Animals studied show 3-BrPA has significant therapeutic activity against liver cancer when given local infusion.
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Female rat "R4" before treatment with 3-bromopyruvate (left) and 4 weeks after treatment with the compound. The tumor is gone from the animal's right shoulder.
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Imatinib (Gleevec)
• It is a inhibitor that designed to specifically target BCR-ABL.
• Imatinib tx decreased the activity of both hexokinase and glucose-6-phosphate dehydrogenase ( G6PD) in leukemia cells.
• Leading to suppression of aerobic glycolysis.
• Imatinib is an antileukemia drug, but also useful for tx of certain solid tumors.
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Oxythiamine
• Inhibits transketolase and pyruvatedehydrogenase.
• Oxythiamine is phosphorylated to yield diphosphate ester which then act as strong competitive inhibitor against normal cofactor TPP ( thiamine pyrophosphate).
• This metabolic inhibitions seems to be responsible, at least in part, for significance anticancer activity in vitro and in vivo.
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By Khirrol Nizam D11A014
TASK 2Calculate total ATP produced from
glycolysis and tricarboxylic acid cycle per one glucose
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Glycolysis
Phase 1,
2 ATP are used ;
1 ATP used for the conversion of glucose to G6P,
1 ATP used for the conversion of F6P to F1,6BP
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Glycolysis
Phase 2,
4 ATP are produced from substrate level phosphorylation;
2 ATPs are produced from the conversion of two molecule of 1,3BPGto two molecule of 3PG
2 ATPs are produced from the conversion of two molecule of PEP to two molecule of pyruvate
Nett ATP produce is 2 ATP only
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Glycolysis
2 NADH is produced from the conversion of two molecule of G3P to 1,3BPG. The 2 NADH may undergo oxidative phosphorylation via;
Glycerol-phosphate shuttle which produced 4 ATP; or
Malate-aspartateshuttle which produced 6 ATP
Sub total ATP produced by glycolysis; 6 ATP or 8 ATP
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Link reaction: pyruvate to acetyl CoA
2 NADH are produced from the conversion of pyruvate to acetyl-CoA
The 2 NADH undergo oxidative phosphorylation which produce 6 ATP
Sub total produced by link reaction is 6 ATP
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Tricarboxylic acid cycle (TCA cycle/ citric acid cycle/ Krebs cycle)
2 ATP are produced from substrate level phosphorylationfrom conversion of two molecule of succinyl-CoA to two molecule of succinate
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Tricarboxylic acid cycle (TCA cycle/ citric acid cycle/ Krebs cycle)
Two cycle of TCA cycle will produce 6 NADH and 2 FADH2
The 6 NADH will undergo oxidative phosphorylationwhich produce 18 ATP
The 2 FADH2 will undergo oxidative phosphorylationwhich produce 4 ATP
Sub total ATP produced by TCA cycle id 24 ATP
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Oxidative phosphorilation
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• ATP yield per glucose molecules
Process ATP Yield per glucose molecule
Glycolysis Substrate level phosphorylationOxidative phosphorylation with 2 NADH:•Glycerol-phosphate shuttle•Malate-aspartate shuttle
2 ATP
4 ATP
2ATP
6 ATP
Link reaction:pyruvate to acetyl-CoA
Oxidative phosphorylation with 2 NADH 6 ATP 6 ATP
TCA Cycle Substrate level phosphorylationOxidatibe phosphorylation with 6 NADHOxidative phosphorylation with 2 FADH2
2 ATP18 ATP4 ATP
2 ATP18 ATP4 ATP
Total 36 ATP 38 ATP
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By Syaffiq Othman D11B039
LIST THE GLYCOGEN STORAGE DISEASE IN ANIMALS AND EXPLAIN THE MECHANISMS OF THE DISEASE
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failure of glycogen to be released from the cell.
Cause by enzyme
Generally,
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Therefore,
glycogen accumulates within the liver and other organs and is unavailable for
conversion to glucose
conversion
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TYPES OF GLYCOGEN STORAGE
DISEASE
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http://emedicine.medscape.com/article/1116574-overview
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• Type I Von Gierke’s
• Type II Pompe’s
• Type III Cori’s
• Type IV Anderson’s
• Type V McArdle’s
• Type VI Her’s
• Type VII Tarui’s
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Von Gierke disease
Glucose-6-phosphatase
deficiency
Affect kidney & liver
Type Ia & Ib
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Pompe’s disease
Cardiomegally
Increase in glycogen
Wide QRS
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Cori’s disease
alpha-1,6-glucosidase deficiency
Affect liver & skeletal muscle
debranchingenzyme
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Andersen’s disease
amylo-1,4-1,6 transglucosidase
deficiency
Affect liver & heart
branching enzyme
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McArdle’s disease
Affect skeletal muscle
Increase in glycogen (cannot release glycogen from muscle)
Myo Phosphorylase deficiency
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Her’s disease
Affect liver
decrease in glycogen (Hypoglycemia)
Hepatic Phosphorylase deficiency
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Tarui’s disease
Affect skeletal muscle and erythrocyte
Phosphofructokinase deficiency
More severe than type V
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“http://www.petmd.com/dog/conditions/endocrine/c_multi_glycogen_storage_disease#.T4xOTdmQk1g”