Cholesterol is an important molecule in the human body – it’s used to synthesize steroid hormones, such as estrogen, testosterone, and molecules that regulate inflammation, as well as vitamin D. Cholesterol is obtained from certain foods in the diet, but it is also synthesized by the liver. The cholesterol molecule is essentially a complex of acetyl units, and precursors of cholesterol exist in the human body as byproducts of other physiological and cellular processes.
The starting molecule for cholesterol is acetyl-CoA, which is a metabolite of cellular respiration and fatty acid oxidation. In the cellular respiration pathway, glucose (six carbons) is phosphorylated and broken down in the presence of oxygen to form pyruvate (three carbons), a process called glycolysis. In the mitochondria, two pyruvate molecules lose carbon dioxide and join with coenzyme A to form acetyl-CoA. The molecule is then usually discussed in the context of the citric acid cycle and electron transport chain.
Three molecules of acetyl-CoA acted on by hydroxymethylglutaryl (HMG)-CoA synthase form HMG-CoA, which is acted on by HMG-CoA reductase (using NADPH as energy) to form mevalonate, starting a cascade of chemical reactions. Further steps utilize ATP to form the isoprenoids, which are then enzymatically condensed to squalene. A visual breakdown of the chemical reactions is available from Renssalaer Polytechnic Institute. The other precursors in the cascade are 5-pyrophosphomevalonate, isopentenyl pyrophosphate (and its interconverted form dimethylallylpyrophosphate), geranyl pyrophosphate and farnesyl pyrophosphate.
Squalene and sterols
In the presence of oxygen, squalene is enzymatically converted to 2,3-oxidosqualene, releasing water. Electron shifts and protonation of the oxidized squalene results in lanosterol. Sterols are precursors of cholesterol and components of the lipoproteins that transport cholesterol in the body such as LDL – particularly methyl sterols. Lanosterol is acted on by the cytochrome P450 enzymes of the endoplasmic reticulum membrane in 19 steps to fully form cholesterol via several metabolites and intermediates. There may also be more than one pathway. An outline of the full steps is available at the Journal of Chemical Education. Intermediates include 32-hydroxylanosterol, 24,25-dihydrolanosterol, 4-alpha-methylcholasta-8(9)-en-3-beta-ol, 8,14-cholestadien-3-beta-ol, 8(9)-cholestanol, zynosterol, desmosterol, lathosterol and 7-dehydrocholesterol. All of these precursors exist in the human body at some point.
Enzymes and defects
Defects in cholesterol synthesis that lead to an accumulation of a cholesterol precursor can occur at any point in the chain of chemical reactions. Genetic defects in a single enzyme can lead to serious and life-altering disorders due to reduced cholesterol synthesis and accumulation of an intermediate molecule. Similarly, too much cholesterol can lead to disorders – particularly the accumulation of fatty deposits containing cholesterol in the cardiovascular system. The precursors cholestenol, desmosterol, lathosterol and squalene are found in LDL, which is considered “bad cholesterol” because of its role in atherosclerosis.
Attention is often focused on the cholesterol consumed in the diet, but the molecule is also made in the human body. This endogenous synthesis requires a large number of chemical reactions, resulting in a long list of cholesterol precursors – starting with glucose and fatty acids.