CVS4 Cholesterol Biochemistry

CHOLESTEROL METABOLISM | Tutorial D-1 CVS

STRUCTURE Hydrophobic compound Consist of:o 4 fused hydrocarbon rings (A, B, C, and D called “steroid nucleus”)o 27 carbon atomso a simple hydroxyl group at C3o a double bond between C5 and C6o an 8-membered hydrocarbon chain attached to carbon 17 in the D ringo a methyl group (carbon 19) attached to carbon 10o a second methyl group (carbon 18) attached to carbon 13

Steroids with 8–10 carbon atoms in the side chain at C-17 and a hydroxyl group at C-3 are classified as sterols

1/3 exist in free (or unesterified) form, 2/3 exist in cholesterol ester in which a

long-chain fatty acid (usually linoleic acid) is attached by ester linkage to the hydroxyl group at C3

Mostly get from synthesis process and rest from food come from animal

SYNTHESIS

130110110177|Gabriella Chafrina| 23/09/13


Stage 1: Biosynthesis of Mevalonateo Synthesis of mevalonate is the commited, rate-limiting step in cholesterol formationo 2 molecule of acetyl CoA condensed and catalyzed by cytolic thiolase acetoacetyl CoA condensed with a 3rd molecule

of acetyl CoA and catalyzed by HMG-CoA synthase 6-carbon compound β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) catalyzed by HMG CoA reductase, uses 2 molecules of NADPH as reducing agent, release CoA (make reaction irreversible) Mevalonic acid (mevalonate)

Stage 2: Formation of Isoprenoid Unitso Mevalonate phosphorylated by ATP by 3 kinases decarboxylation active isprenoid unit, isopentenyl diphosphate

Stage 3: 6 Isoprenoid Units form Squaleneo Isopentyl diphosphate isomerized by a shift of the double bond dimethylallyl diphosphate condensed with another

molecule isopentenyl diphosphate geranyl diphosphate condensed with isopentenyl diphosphate farnesyl diphosphate 2 molecule of farnesyl diphosphate condense at diphosphate end squalane

Stage 4: Formation of Lanosterolo Squalene mixed function oxidase in ER, squalene epoxidase squalene 2,3-epoxide cyclization occurs, catalyzed by

oxidosqualene lanosterol cyclase (methyl group on C14 is transferred to C13 and on C8-C14) Lanosterol Stage 5: Formation of Cholesterol

o Lanosterol The methyl groups on C14 an C4 are removed 14-desmethyl lanosterol Zymosterol double bond at C8-C9 is subsequently moved to C5-C6 (25-dehydrocholesterol) Desmosterol double bond of the side chain is reduced Cholesterol



Stage 1: Stage 2: Stage 3: Stage 4 & 5:

TRANSPORT Cholesterol is transported in plasma in lipoproteins Lipoprotein:

o Is for transport vehicle and provide delivery & pick up serviceso Classification: (categorized according to density)

Chylomicron Form in mucosal epithelial cells of small intestine Transport dietary lipids to adipose tissue for storage Chylomicrons lacteal lymph venous blood systemic circulation Hepatocyte remove chylomicron remnant from blood

Very Low Density Lipoprotein Transport triglyceride synthesized by hepatocytes to adipose for storage Form in hepatocytes

Low Density Lipoprotein Carry about 75% of total cholesterol “bad cholesterol” Deliver cholesterol from liver to other parts of the body for use in the repair of cell membrane,

synthesis of steroid hormone and bile salts When ↑, LDL deposits cholesterol in and around smooth muscle fibers in arteries fatty plaque

Intermediate Density Lipoprotein Rarely detected in blood 50% of IDL degraded in liver, rest become LDL


↓ size

↑ density

↓ triglyceride


High Density Lipoprotein Remove excess cholesterol from body cells & blood transport to liver elimination Alike protein Less cholesterol phosphate

Exogenous (Intestinal) Pathway1) Dietary fats are absorbed by small intestine and repackaged as chylomicrons, accompanied by apo B-48. Chylomicrons are large

particles, particularly rich in triglycerides, that enter the circulation via the lymphatic system2) Apo E and subtypes of apo C are transferred to chylomicrons from HDL particles in the bloodstream3) Apo C (subtype CII) enhances interactions of chylomicrons with lipoprotein lipase (LPL) on the endothelial surface of adipose and

muscle tissue. This reaction hydrolyzes the triglycerides within chylomicrons into free fatty acids (FFA), which are stored by adipose tissue or used for energy in cardiac and skeletal muscle

4) Chylomicron remnants are removed from the circulation by the liver, mediated by apo E5) One fate of cholesterol in the liver is incorporation into bile acids, which are exported to the intestine, completing the exogenous

pathway cycle

Endogenous (Hepatic) PathwayBecause dietary fat availability is not constant, endogenous pathway provides a reliable supply of triglycerides for tissue energy needs:6) Dietary fats are absorbed by the small intestine and repackaged as chylomicrons, accompanied by apo B-48. Chylomicrons are

large particles, particularly rich in triglycerides, that enter the circulation via the lymphatic system7) Apo E and subtypes of apo C are transferred to chylomicrons from HDL particles in the bloodstream8) Apo C (subtype CII) enhances interactions of chylomicrons with lipoprotein lipase (LPL) on the endothelial surface of adipose and

muscle tissue. This reaction hydrolyzes the triglycerides within chylomicrons into free fatty acids (FFA), which are stored by adipose tissue or used for energy in cardiac and skeletal muscle

9) Chylomicron remnants are removed from the circulation by the liver, mediated by apo E10) One fate of cholesterol in the liver is incorporation into bile acids, which are exported to the intestine, completing the exogenous

pathway cycle



EXCRETION Cholesterol is excreted from the body via the bile either in the unesterified form or after conversion into bile acids in the liver Primary bile acids synthesized in liver changes by intestinal bacteria secondary bile acids Pathway: in bile acid form to intestine some reabsorbed in ileum through enterohepatic circulation (aorta circulation)

to liver. Bile acids not absorbed will come out as a faeces

Reference: Harper’s Illustrated Biochemistry 28th edition; Lippincott Illustrated Reviews Biochemistry 4th edition; Lilly Pathophysiology of Heart Disease; Marks’ Basic Medical Biochemistry: A Clinical Approach, 2nd edition


CVS4 Cholesterol Biochemistry

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