Biochemistry Group 7 Hanif Amin Khayeer Al-Farouq Syaffiq Othman - - PowerPoint PPT Presentation

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

Glycolysis diagram

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
• f

glycolysis at the step

• f

phosphorylation of glucose by hexokinase.

• Its reduced avaibality of glucose for glycolysis.
• A clinical trial suggest that 2-DG at dosses up

to 250mg/kg appears safe for use combination with 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 pyruvate

dehydrogenase.

• 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 2 Calculate 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 1,3BPG to 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-aspartate

shuttle 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 phosphorylation from 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
• xidative phosphorylation

which produce 18 ATP

• The 2 FADH2 will undergo
• xidative phosphorylation

which 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 phosphorylation Oxidative 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 phosphorylation Oxidatibe phosphorylation with 6 NADH Oxidative phosphorylation with 2 FADH2 2 ATP 18 ATP 4 ATP 2 ATP 18 ATP 4 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 debranching enzyme

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_mult i_glycogen_storage_disease#.T4xOTdmQk1g”