Cholesterol, Steroid and Isoprenoid Biosynthesis


Steroids, sterols, and many other natural products all derive from isoprenoid building blocks via two common biosynthetic pathways. The subsequent processing of the structural core yields specific products that possess diverse structures and biological activities.

Keywords: sterols; bile acids; squalene; mevalonate; deoxyxylulose phosphate pathway; steroidogenesis; biosynthetic defects

Figure 1.

Regulation of HMGCoA 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 HMGCoA reductase leads to inhibition of SREBP cleavage and degradation of HMGCoA reductase, respectively.

Figure 2.

Classical pathway from acetate to isoprene units. Condensation of three acetate moieties yields HMGCoA. Reduction of HMGCoA to mevalonate by HMGCoA 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 (Δ24‐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 17β HSD enzymes complete the synthesis of testosterone and oestradiol (fourth row), and 5α‐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; α and β 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 7α‐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 7α‐hydroxylation by other enzymes account for another ∼25%. Ring modification by HSD3B7, AKR1D1, and AKR1C4 yield the 5α‐reduced, 3α,7α‐diol unit, and the key bile acids also incorporate a 12α‐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 3α,7α,12α‐trihydroxy‐5β‐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 γ‐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.


Further Reading

Auchus RJ and Miller WL (2001) The principles, pathways, and enzymes of human steroidogenesis. In: DeGroot LJ and Jameson JL (eds) Endocrinology, pp. 1616–1631. Philadelphia, W.B. Saunders.

Bonanno JB, Edo C, Eswar N et al. (2001) Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis. Proceedings of the National Academy of Sciences of the United States of America 98: 12896–12901.

Eisenreich W, Rohdich F and Bacher A (2001) Deoxyxylulose phosphate pathway to terpenoids. Trends in Plant Science 6: 78–84.

Horton JD, Shah NA, Warrington JA et al. (2003) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proceedings of the National Academy of Sciences of the United States of America 100: 12027–12032.

Istvan ES, Palnitkar M, Buchanan SK and Deisenhofer J (2000) Crystal structure of the catalytic portion of human HMG‐CoA reductase: insights into regulation of activity and catalysis. EMBO Journal 19: 819–830.

Kelley RI and Herman GE (2001) Inborn errors of sterol biosynthesis. Annual Review of Genomics and Human Genetics 2: 299–341.

Laden BP, Tang Y and Porter TD (2000) Cloning, heterologous expression, and enzymological characterization of human squalene monooxygenase. Archives of Biochemistry and Biophysics 374: 381–388.

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Miller WL (1988) Molecular biology of steroid hormone synthesis. Endocrine Reviews 9: 295–318.

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Russell DW (2003) The enzymes, regulation, and genetics of bile acid synthesis. Annual Review of Biochemistry 72: 137–174.

Sato R, Goldstein JL and Brown MS (1993) Replacement of serine‐871 in hamster 3‐hydroxy‐3‐methylglutaryl‐CoA reductase prevents phosphorylation by AMP‐activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion. Proceedings of the National Academy of Sciences of the United States of America 15: 9261–9265.

Sever N, Song BL, Yabe D et al. (2003) Insig‐dependent ubiquitination and degradation of mammalian HMG‐CoA reductase stimulated by sterols and geranylgeraniol. Journal of Biological Chemistry 278: 52479–52490.

Shyadehi AZ, Lamb DC, Kelly SL et al. (1996) The mechanism of the acyl‐carbon bond cleavage reaction catalyzed by recombinant sterol 14 alpha‐demethylase of Candida albicans(other names are: lanosterol 14 alpha‐demethylase, P‐45014DM, and CYP51). Journal of Biological Chemistry 271: 12445–12450.

Tansey TR and Shechter I (2000) Structure and regulation of mammalian squalene synthase. Biochimica et Biophysica Acta 1529: 49–62.

Yang T, Espenshade PJ, Wright ME et al. (2002) Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to Insig‐1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110: 489–500.

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Auchus, Richard J, and Adams, Christopher M(Sep 2005) Cholesterol, Steroid and Isoprenoid Biosynthesis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0001393]