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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. HMG- CoA reductase (HMGR) for control the amount of cholesterol in the cell. Hydroxymethyl-glutaryl- CoA (HMG-CoA) is the precursor for cholesterol biosynthesis in the branched pathway of isoprenoid metabolism in mammalian cells.
2 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 HCO3- transport 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/CO2respiration
O2increases extraction of energy from glucose 18x Erythrocytes transport O2/CO2
Hb transports O2in 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
