Mechanistic basis of enzyme-targeted drugs
Enzyme inhibitors as drugs
Enzyme inhibitors are a significant category of drugs: metabolism is critically important to our
biological homeostasis.
Why is hypercholesterolemia a health issue?
Excess cholesterol in the bloodstream is deposited in the walls of blood vessels, particularly in the
arteries that supply blood to the heart (coronary arteries). It means that need more blood pressure to
pump the blood to the tissue. Heart is under a very high pressure.
Life-acquired hypercholesterolemia
Hypolipoproteinemia or hyperlipidaemia is the condition of abnormally elevated levels of any or all
lipids and/or lipoproteins in the blood.
Causes of abnormal cholesterol and triglyceride levels:
Being overweight or obese. A metabolic syndrome!
Excessive alcohol use
Fatty diets that are high in saturated fats. (found mainly in red meat, egg yolks, and high-fat
dairy products) and trans fatty acids (found in commercial processed food products).
Lack of exercise.
Smoking (which reduces HDL “good” cholesterol).
Cholesterol is a vital constituent of cell membranes and a precursor to steroid hormones. Very
important for membranes, but should not get too much, just need in the right level.
All of cholesterol’s carbon atoms can be considered as derived from 27 acetates (carbons).
Cholesterol is converted to the cholesteryl ester for storage or for packaging into VLDL (very low
density lipoprotein) by liver.
Cholesterol is transported in blood plasma by lipoproteins but its deposition in arteries is associated
with heart disease. As cholesterol is not metabolised by cells it is a potential toxin. The liver plays a
key role in regulating the recycling of cholesterol. Different proteins are identified by different
receptors because of differences in protein associated with their membranes.
Cholesterol also can be converted by the liver to a bile acid such a cholate.
Cells either synthesize cholesterol themselves or they import it from LDL.
Cholesterol uptake is mediated via LDL receptor-mediated endocytosis in mammalian cells. This can
be used to maintain the integrity of the cell membrane and regulates LDL receptor synthesis. HMGCoA reductase (HMGR) for control the amount of cholesterol in the cell. Hydroxymethyl-glutarylCoA (HMG-CoA) is the precursor for cholesterol biosynthesis in the branched pathway of isoprenoid
metabolism in mammalian cells.
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HDL has the opposite function to LDL and removes excess cholesterol from tissues. The liver is the
only organ capable of removing excess cholesterol from the body by its conversion to bile acids for
digestion.
Inhibition of HMGR can reduces endogenous cholesterol synthesis.
The statin compounds like substrate/product structural mimics because they interact with the active
site in a manner similar to Michaelis complex (often referred to as ES/EP).
Type 1 statins are lactone fungal derivatives that are hydrolysed enzymatically in vivo to active
hydroxyl-acid forms. Indeed, the synthetic inhibitor atorvastatin (Lipitor) is one of the most widely
prescribed drugs in the USA and can reduce serum cholesterol levels for heterozygote FH by 40-50%.
Isoenzyme selective inhibitors of carbonic anhydrase
Introduction to glaucoma
Fluid is continually secreted into the eye and is thought to be coupled to Na+ and HCO3transport out of cells.
Drainage is either blocked or too slow.
Miotics reduce the size of the pupil.
Beta blockers act on the receptor mediated signal to produce fluid.
Inhibiting the enzyme carbonic anhydrase-II partitions more CO2 to direct diffusion out of the eye
and thereby reduces fluid inflow, decreasing IOP.
Carbonic anhydrases:
7 class 1 isoenzymes (I-VII) found in human tissues.
4 cytosolic isoenzymes: human CA I, II, III & VII-29 kDa proteins.
Catalyses the hydration of dissolved CO2
Maintains substrate/product in equilibrium
The role of CA in O2/CO2 respiration
O2 increases extraction of energy from glucose 18x
Erythrocytes transport O2/CO2
Hb transports O2 in red blood cells
Hb also transports CO2/CO3- in red blood cells
Tissue CA interconverts CO2/CO3- prior to transport
Plasma CO3- transport is also significant
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