Cholesterol Synthesis

Cholesterol Synthesis - Molecular Biochemistry II...

Info iconThis preview shows pages 1–10. Sign up to view the full content.

View Full Document Right Arrow Icon
Cholesterol Synthesis Copyright © 1999-2008 by Joyce J. Diwan. All rights reserved. Molecular Biochemistry II
Background image of page 1

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Hydroxymethylglutaryl-coenzyme A ( HMG-CoA ) is the precursor for cholesterol synthesis. HMG-CoA is also an intermediate on the pathway for synthesis of ketone bodies from acetyl-CoA. The enzymes for ketone body production are located in the mitochondrial matrix. HMG-CoA destined for cholesterol synthesis is made by equivalent, but different, enzymes in the cytosol . CH 2 C CH 2 C OH O SCoA CH 3 C O - O hydroxymethylglutaryl-CoA
Background image of page 2
w HMG-CoA is formed by condensation of acetyl-CoA & acetoacetyl-CoA, catalyzed by HMG-CoA Synthase . w HMG-CoA Reductase catalyzes production of mevalonate from HMG-CoA. H 3 C C CH 2 C O O SCoA H 3 C C O SCoA HSCoA CH 2 C CH 2 C OH O SCoA CH 3 C O - O H 2 O + acetoacetyl-CoA hydroxymethylglutaryl-CoA acetyl-CoA HMG-CoA Synthase
Background image of page 3

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
The carboxyl of HMG that is in ester linkage to the CoA thiol is reduced to an aldehyde , and then to an alcohol . NADPH serves as reductant in the 2-step reaction. Mevaldehyde is thought to be an active site intermediate, following the first reduction and release of CoA. + HSCoA H 2 C C CH 3 HO CH 2 C - O O C SCoA O H 2 C C CH 3 HO CH 2 C - O O H 2 C OH 2NADP + 2NADPH HMG-CoA mevalonate HMG-CoA Reductase
Background image of page 4
HMG-CoA Reductase is an integral protein of endoplasmic reticulum membranes. The catalytic domain of this enzyme remains active following cleavage from the transmembrane portion of the enzyme. The HMG-CoA Reductase reaction, in which mevalonate is formed from HMG-CoA, is rate- limiting for cholesterol synthesis. This enzyme is highly regulated and the target of pharmaceutical intervention.
Background image of page 5

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Mevalonate is phosphorylated by 2 sequential Pi transfers from ATP, yielding the pyrophosphate derivative. ATP-dependent decarboxylation, with dehydration, yields isopentenyl pyrophosphate . H 2 C C CH 3 HO CH 2 C - O O CH 2 OH H 2 C C CH 2 CH 2 O P O P O - O O - O O - CH 3 H 2 C C CH 3 HO CH 2 C - O O CH 2 O P O P O - O O - O O - CO 2 ATP ADP + P i 2 ATP 2 ADP mevalonate 5-pyrophosphomevalonate (2 steps) isopentenyl pyrophosphate
Background image of page 6
Isopentenyl pyrophosphate is the first of several compounds in the pathway that are referred to as isoprenoids , by reference to the compound isoprene . isoprene H 2 C C C CH 2 CH 3 H isopentenyl pyrophosphate H 2 C C C H 2 H 2 C CH 3 O P O - O O P O - O O -
Background image of page 7

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Isopentenyl Pyrophosphate Isomerase inter-converts isopentenyl pyrophosphate & dimethylallyl pyrophosphate . Mechanism: protonation followed by deprotonation. H 2 C C CH 2 CH 2 O P O P O - O O - O O - CH 3 H 3 C C CH CH 2 O P O P O - O O - O O - CH 3 isopentenyl pyrophosphate dimethylallyl pyrophosphate
Background image of page 8
Prenyl Transferase catalyzes head-to-tail condensations: w Dimethylallyl pyrophosphate & isopentenyl pyrophosphate react to form geranyl pyrophosphate . w
Background image of page 9

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Image of page 10
This is the end of the preview. Sign up to access the rest of the document.

Page1 / 34

Cholesterol Synthesis - Molecular Biochemistry II...

This preview shows document pages 1 - 10. Sign up to view the full document.

View Full Document Right Arrow Icon
Ask a homework question - tutors are online