Figure 1. Regulation of HMG-CoA reductase by sterols and Insig proteins. (a) Activation of SREBP pathway and cholesterol synthesis and uptake when cellular sterol content is low. (b) Sterol-dependent interaction of Insig proteins with sterol-sensing domains of SCAP and HMG-CoA reductase leads to inhibition of SREBP cleavage and degradation of HMG-CoA reductase, respectively.

Figure 2. Classical pathway from acetate to isoprene units. Condensation of three acetate moieties yields HMG-CoA. Reduction of HMG-CoA to mevalonate by HMG-CoA reductase is the rate-limiting step in cholesterol biosynthesis. Phosphorylation and decarboxylation of mevalonate yields IPP and DMAPP. Small, straight arrows indicate atoms where chemistry occurs in subsequent step; curved arrows show electron flow during decarboxylation step.

Figure 3. Synthesis of cholesterol from lanosterol. The DHCR24 (²⁴-reductase) enzyme can reduce all the sterols shown on the left side. The key carbon atoms are numbered in the lanosterol structure (top), and all carbon atoms of cholesterol are numbered (bottom).

Figure 4. Steroid biosynthesis. Cholesterol is converted to pregnenolone by CYP11A1, and subsequent enzymes yield the mineralocorticoid aldosterone (top row), the glucocorticoid cortisol (second row), or precursors of active androgens and oestrogens (third row). The 17 HSD enzymes complete the synthesis of testosterone and oestradiol (fourth row), and 5-reductases convert testosterone to the most potent endogenous androgen, dihydrotestosterone (bottom). The steroid ring structure (21-carbon) is shown at lower right part of the figure. The carbon atoms are numbered and rings are lettered by convention; and refer to the steroichemistry of substituents on tetrahedral carbon atoms.

Figure 5. Major metabolic pathways from cholesterol to bile acids. The key enzymes and representative structures for each phase of bile acid synthesis are shown. For the initiation process, the 7-hydroxylation of cholesterol by CYP7A1 is the key initial step, accounting for ~75% of bile acid synthesis, and alternative pathways in which 24, 25, or 27-hydroxylation precedes 7-hydroxylation by other enzymes account for another ~25%. Ring modification by HSD3B7, AKR1D1, and AKR1C4 yield the 5-reduced, 3,7-diol unit, and the key bile acids also incorporate a 12-hydroxyl group, added by CYP8B1. These C₂₇ diols and triols are side-chain oxidized and converted to CoA esters by CYP27A1, bile acid CoA ligase, 2-methylacyl-CoA racemase, branched-chain acyl-CoA oxidase (ACOX2), d-bifunctional protein, and peroxisomal thiolase 2. The two principal bile acids in human beings, taurocholic acid and glycocholic acid, derive from conjugation of the intermediate 3,7,12-trihydroxy-5-cholan-24-one-CoA with taurine or glycine, respectively.

Figure 6. The DXP pathway to isoprene units. The two carbon atoms of pyruvate (a, b) are added to d-glyceraldehyde-3-phosphate by DXP-synthase, yielding 1-deoxy-d-xylulose 5-phosphate (DXP). DXP-reductoisomerase uses retro-aldol chemistry to isomerize DXP to the bracketed intermediate (note the reorientation of carbon atoms labelled a, b, and c), which is reduced with NADPH to 2C-methyl-d-erythrose 4-phosphate (MEP). Next, 4-diphosphocytidyl-2C-methyl-d-erythritol synthase adds a CMP moiety from CTP to MEP to form 4-diphosphocytidyl-2C-methyl-d-erythritol (CDP-ME). The -phosphate of ATP is added to the 2-hydroxyl by CDP-ME kinase, which yields 4-diphosphocytidyl-2C-methyl-d-erythritol 2-phosphate (CDP-ME-P). Finally, the CMP is eliminated by ME-cDP-synthase, yielding the cyclic diphosphate 2C-methyl-d-erythritol 2,4-cyclodiphosphate (MEcDP). The subsequent steps that convert MEcDP to isopentenyl- and dimethylallyl diphosphates (IPP and DMAPP) are not yet understood.