Cholesterol is synthesized de novo from acetyl CoA, which is transformed in an initial sequence of 15 reactions into lanosterol. The synthesis of cholesterol from lanosterol is classically said to follow either of two major routes, one in which reduction of the double bond at position 24 in the isooctyl side chain is the final step (cholesterol synthesis via desmosterol, the Bloch pathway (Bloch 1965) and one in which this reduction is the first step (cholesterol biosynthesis via lathosterol, the Kandutsch-Russell (KR) pathway (Kandutsch & Russell 1960).
More recent tracer studies in intact mice and human and mouse cell lines support a revised view of the physiological roles of these two pathways (Mitsche et al. 2015). These studies indicate that the Bloch pathway is the predominant one in most tissues, notably testes and adrenal gland, and is constitutive. Little flux through the complete KR pathway was found in any tissue. Instead, Mitsche et al. observed a modified form of the pathway, in which delta(24)-sterol reductase (DHCR24) reduced zymosterol, a Bloch pathway intermediate, to zymostenol, a KR intermediate, which was then metabolized via the last three steps of the KR pathway to form cholesterol. Usage of this pathway was observed in skin, preputial glands and brain. Here, these reactions are grouped into two pathways. “Zymostenol biosynthesis via lathosterol” contains the initial nine steps of the KR pathway that now appear to play a minor role in cholesterol biosynthesis. “Cholesterol biosynthesis from zymosterol (modified KR pathway)” contains the reaction that generates ZYMSTNL and the three KR reactions that convert it to cholesterol (Mietsche et al. 2015).
The 7-dehydrocholesterol produced by the modified KR pathway in skin is the starting point for the synthesis of D vitamins. Defects in several of the enzymes involved in this process are associated with human disease and have provided useful insights into the regulatory roles of cholesterol and its synthetic intermediates in human development (Gaylor 2002; Herman 2003; Song et al. 2005).
