Biochemistry Group 7

Hanif Amin

Khayeer Al-Farouq

Syaffiq Othman

Khirrol Nizam

LIST CHEMICAL THAT INHIBIT PARTICULAR ENZYME IN GLYCOLYSIS

AND THEIR MECHANISM OF INHIBITION

By Hanif Amin D11B043

Khayeer Al-Farouq D11B040

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

Glycolysisdiagram

Enzyme inhibition • Competitive enzyme inhibition – competitive

blocker at the active site

• Non-competitive enzyme inhibition – non-

competitive blocker causes conformational changes

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

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.

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.

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.

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.

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.

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.

By Khirrol Nizam D11A014

TASK 2Calculate total ATP produced from

glycolysis and tricarboxylic acid cycle per one glucose

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

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

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

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

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

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

Oxidative phosphorilation

• 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

By Syaffiq Othman D11B039

LIST THE GLYCOGEN STORAGE DISEASE IN ANIMALS AND EXPLAIN THE MECHANISMS OF THE DISEASE

failure of glycogen to be released from the cell.

Cause by enzyme

Generally,

Therefore,

glycogen accumulates within the liver and other organs and is unavailable for

conversion to glucose

conversion

TYPES OF GLYCOGEN STORAGE

DISEASE

http://emedicine.medscape.com/article/1116574-overview

• 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

Von Gierke disease

Glucose-6-phosphatase

deficiency

Affect kidney & liver

Type Ia & Ib

Pompe’s disease

Cardiomegally

Increase in glycogen

Wide QRS

Cori’s disease

alpha-1,6-glucosidase deficiency

Affect liver & skeletal muscle

debranchingenzyme

Andersen’s disease

amylo-1,4-1,6 transglucosidase

deficiency

Affect liver & heart

branching enzyme

McArdle’s disease

Affect skeletal muscle

Increase in glycogen (cannot release glycogen from muscle)

Myo Phosphorylase deficiency

Her’s disease

Affect liver

decrease in glycogen (Hypoglycemia)

Hepatic Phosphorylase deficiency

Tarui’s disease

Affect skeletal muscle and erythrocyte

Phosphofructokinase deficiency

More severe than type V

“http://www.petmd.com/dog/conditions/endocrine/c_multi_glycogen_storage_disease#.T4xOTdmQk1g”