|Cholesterol synthesis pathway. The mevalonate pathway leads to lanosterol, which can then be diverted into either the Bloch pathway, producing cholesterol via desmosterol, or the Kandutsch-Russell pathway, via 7-dehydrocholesterol. Two other branches also diverge from the mevalonate pathway. Isoprenoids are produced by geranylgeranyl-diphosphate synthase (GGPPS) acting twice to convert farnesyl diphosphate to geranylgeranyl diphosphate, and flux through the shunt pathway occurs when SM acts twice to convert squalene 2,3-epoxide into diepoxysqualene, eventually leading to the production of 24(S),25-epoxycholesterol. Intermediates and enzymes in this shunt pathway are not yet fully elucidated but are presumed to follow the Kandutsch-Russell pathway. MK, mevalonate kinase; PMK, phosphomevalonate kinase; MVD, diphosphomevalonate decarboxylase; FPPS, farnesyl-pyrophosphate synthase; SQS, squalene synthase; LDM, lanosterol 14α-demethylase; SC5D, sterol C5-desaturase.
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The human body needs cholesterol to maintain membrane fluidity, and it acts as a precursor molecule for several important biochemical pathways. Its regulation requires strict control, as it can cause problems if it’s produced in excess. In 1964, Konrad Bloch received a Nobel Prize for his work elucidating the mechanisms of cholesterol synthesis. His work eventually contributed to the discovery of statins, drugs used today to lower blood cholesterol levels.
The biosynthesis of cholesterol is a complex process with more than 20 steps. One of the first enzymes is 3-hydroxy-3-methylglutaryl-CoA reductase, also known as HMGCR, the main target of statins. As links between intermediates in cholesterol synthesis and various diseases are being discovered continually, more information about the regulatory role of the post-HMGCR pathway is needed.
In a recent minireview in The Journal of Biological Chemistry, Laura Sharpe and Andrew Brown of the University of New South Wales describe multiple ways various enzymes other than HMGCR are implicated in the modulation of cholesterol synthesis. One such enzyme is squalene monooxygenase, which, like HMGCR, can be destroyed by the proteasome when cholesterol levels are high.
The minireview also explains how pathway intermediates can have functions distinct from those of cholesterol. For example, intermediate 7-dehydrocholesterol usually is converted to cholesterol by the enzyme DHCR7 but is also a vitamin D precursor. To synthesize the enzymes necessary to make cholesterol, SREBPs, short for sterol regulatory element binding proteins, have special functions. Along with transcriptional cofactors, they activate gene expression in response to low sterol levels and, conversely, are suppressed when there is enough cholesterol around. Additionally, SREBPs control production of nicotinamide adenine dinucleotide phosphate, or NADPH, which is the reducing agent required to carry out the different steps in the pathway.
Lipid carrier proteins also can facilitate cholesterol synthesis. One example is SPF, or supernatant protein factor, which transfers substrate from an inactive to an active pool or from one enzyme site to another. Furthermore, translocation of several cholesterogenic enzymes from the endoplasmic reticulum to other cell compartments can occur under various conditions, thereby regulating levels and sites of intracellular cholesterol accumulation.
Swathi Parasuraman (email@example.com) is a graduate student in the life science and medical bioscience department at Waseda University in Tokyo.