Cytochrome cholesterol biosynthesis

A number of cytochrome P450 enzymes are involved in the conversion of acetate to sterols and bile acids (Figure 9.6). The participation of P450 enzymes in pathways of cholesterol biosynthesis and elimination demonstrate their important role in cholesterol homeostasis. Lanosterol 14a-desmethylase, encoded by CYP51A1, is a pivotal P450 involved in cholesterol biosynthesis. The synthesis of bile acids from... 

In considering the mechanism of action of azoles on sterol biosynthesis in powdery mildew (see figure 4), we should discuss a variation in the biosynthetic sequence to the end-product. The occurrence of obtusifoliol and 24-methylenedihydrolanosterol following azole treatment confirms that the oxidative removal of the C-14-methyl group by the cytochrome P-450 system is also inhibited. The fact that side chain alkylation is performed prior to this step in powdery mildew seems worthy of note, reflecting as it does a principal difference to cholesterol biosynthesis in mammals. 

Fig. 8. A schematic diagram showing cellular processes known to require SCP2. The reactions in cholesterol biosynthesis and esterification have been shown for liver. The reactions involving cholesterol transport from cytoplasmic lipid inclusion droplets to mitochondria have been demonstrated in endocrine tissues. Choi and C. cholesterol ACAT, acyl-CoA cholesterol acyl transferase C.E., cholesterol ester SEH, sterol ester hydrolase (hormone-dependent) P-450s,, cytochrome P-450 cholesterol side-chain cleavage enzyme PREG, pregnenolone.

See also Figure 1.13, Protein Targeting, Programmed Destruction of Proteins, Cholesterol Biosynthesis, Biosynthesis of Glycoconjugates, Cytochrome P-450... 

Trzaskos, J., S. Kawata, and J.L. Gaylor (1986). Microsomal enzymes of cholesterol biosynthesis. Purification of lanosterol 14a-methyl demethy-lase cytochrome P-450 from hepatic microsomes. J. Biol Chem. 261, 14651-14657. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Like the a2ole derivatives, it inhibits the biosynthesis of ergosterol. However, naftifine [65472-88-0] does not inhibit the cytochrome P-450 dependent C-14-demethylase, but the epoxidation of squalene. Squalene epoxidase cataly2es the first step in the conversion of squalene via lanosterol to ergosterol in yeasts and fungi or to cholesterol in mammalian cells. The squalene epoxidase in C. albicans is 150 times more sensitive to naftifine, C2 H2 N, than the en2yme in rat fiver (15). Naftifine is available as a 1% cream. 

NADPH), oxygen, and a specific cytochrome P450. The rate-limiting step in steroid biosynthesis is the conversion of cholesterol to pregnenolone (Fig. 60.1). 

Cytochromes P450 form a very large group of heme enzymes that catalyze the hydroxylation of a variety of substrates. They are important in drug metabolism, in cholesterol and steroid hormone biosynthesis, and in numerous other pathways. They have been found to participate in reactions other than hydroxyla-tions. 

The rate-limiting step in progestin biosynthesis is the side-chain cleavage of cholesterol to pregnenolone taking place in the mitochondria. At least three steps in the cholesterol side-chain cleavage (SSC) reaction may be under hormonal regulation [72,73]. FSH stimulates the synthesis of the SSC cytochrome P-450 which results in the stimulation of SSC activity [74]. 

Fig. 2. Pathway of biosynthesis of the glucocorticoid, cortisol, in the adrenal cortex. Cholesterol, from stores in cholesteryl esters or from other sources (see text) is converted via mitochondrial cytochrome P-450SCC (cholesterol side-chain cleavage enzyme) to pregnenolone, which then is successively converted by the microsomal enzymes cytochrome P-450,7 (17a-hydroxylase), 3 j8-hydroxysteroid dehydrogenase/ isomerase and cytochrome P-450c2, (21-hydroxylase) to 11-deoxycortisol, followed by conversion by the mitochondrial cytochrome P-450ll(3 (11/3-hydroxylase) to cortisol. The short-term action of ACTH in stimulation of steroidogenesis is to increase the availability of cholesterol for conversion by cytochrome P-450scc. From Ref. 9.

Digitalis lanata, where the pro-4R hydrogen of MVA occupied the pro-24S position and trans-addition of hydrogen was deduced. The demethylation steps in the biosynthesis of cholesterol have received much attention. In rat liver microsomes the removal of the 14a -methyl group of 24,25-dihydrolanosterol led to the formation of a A8,14-diene (84), and neither a A8(14)-ene nor a A8,14,24-triene were obligate intermediates in cholesterol synthesis.141,142 14a-Demethylation, which was preceded by A24,25-reduction in rat liver system, involved cytochrome P450, whilst the next step in the biosynthesis of cholesterol, AI4-reduction, and the reduction of the A7- and A5,7-sterols were completely inhibited by the drug AY-9944.142,143 In yeast, A14-reduction probably involved trans-addition of a hydride ion from NADPH and a proton from the medium at the 14a- and 15/3-positions, respectively.144... 

Cholesterol 7a-hydroxylase, a cytochrome P450-dependent enzyme, catalyzes the first and rate-limiting step in the biosynthesis of bile acids from cholesterol. Potential mechanisms for regulation of the enzyme have been extensively studied. 

The side chain cleavage of cholesterol, producing pregnenolone, is catalyzed by cytochrome P450JCC. This is the initial step in the biosynthesis of several steroid hormones. In this assay, the initial product, pregnenolone, is quantitatively converted to progesterone by treatment with cholesterol oxidase, which increases by about 10-fold the sensitivity of the assay. 

Research on the mechanism of the onset of hypercholesterolemia during a state of marginal vitamin C deficiency (6,21,22) has led to the finding that ascorbate is necessary for cholesterol transformation to bile acids (23) at the rate-limiting reaction of bile-acid biosynthesis. That limiting step is the 7 -hydroxylation of cholesterol (6,24r-26). The action of ascorbate on 7 -hydroxylation is not a direct one because in vitro added L-ascorbic acid has no effect (24,27). The effect is mediated by the intervention of ascorbate in the metabolism of cytochrome P450 in the endoplasmatic reticulum of the hepatal cell (6,24), Through a... 

Cholesterol metabolism and bile acid biosynthesis. At least seven cytochrome P-450 enzymes play critical roles in the conversion of acetate into sterols and bile acids. Key among these are CYP51A1, CYP7A1, CYP7B1, and CYP39A1. The roles of each of these enzymes are beyond the scope of this article, but some excellent reviews and texts are available on the topic. 

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