A comprehensive machine-readable view of the mammalian cholesterol biosynthesis pathway

Abstract

Graphical abstractWe present the pathways leading to cholesterol, epoxy-cholesterol and oxysterol synthesis.

Sterols and oxysterols in plasma from Smith-Lemli-Opitz syndrome patients

“…It is an autosomal recessive disorder resulting from deficiency of the enzyme 7-dehydrocholesterol reductase (DHCR7, EC 1.3.1.21, 3β-hydroxysterol Δ 7 -reductase) [2]. DHCR7 reduces the Δ 7 -double bond in 7-dehydrodesmosterol (7-DHD, cholesta-5,7,24-trien-3β-ol) and in 7-dehydrocholesterol (7-DHC, cholesta-5,7-dien-3β-ol) leading to the formation of desmosterol (cholesta-5,24-dien-3β-ol) and cholesterol (cholest-5-en-3β-ol) via the Bloch and Kandutsch-Russel pathways, respectively (Figure 1A) [3]. SLOS patients show decreased levels of cholesterol and increased levels of 7-DHC and its isomer 8-dehydrocholesterol (8-DHC, cholesta-5,8(9)-dien-3β-ol) in serum and tissues [4].…”

Controlling Cholesterol Synthesis beyond 3-Hydroxy-3-methylglutaryl-CoA Reductase (HMGCR)

“…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 (75) pathway. We will illustrate these with recent work on post-HMGCR enzymes.…”

Mathematically modelling the dynamics of cholesterol metabolism and ageing

“…In recent years however, several groups have adopted a systems level approach to investigating lipid metabolism Mooney et al, 2016). The majority of these models have centred on specific metabolic processes, including those directed at lipoprotein metabolism (Hubner et al, 2008;Shorten and Upreti, 2005;Sips et al, 2014), cholesterol biosynthesis (Bhattacharya et al, 2014;Kervizic and Corcos, 2008;Mazein et al, 2013;Watterson et al, 2013), reverse cholesterol transport (Lu et al, 2014), adipocyte metabolism (Micheloni et al, 2015), hepatocyte metabolism (Jerby et al, 2010), cholesterol regulatory enzymes (Chapman et al, 2010), whole-body plasma cholesterol metabolism (van de Pas et al, 2012) and enterohepatic circulation of bile acids (Mishra et al, 2014). These models all have noteworthy features and have added to our understanding of lipid metabolism.…”