chapter 30
Endocrine Metabolism I: Introduction
f i g u r e : 3 0 -2
Biosynthesis of steroid hormones from cholesterol. The different pathways occur to varying extent in adrenals, gonads,
and placenta. The systematic names for cytochrome P-450 enzymes, namely CYP followed by a number, are given in
parentheses. CYPI1B2 and CYP17 possess multiple enzyme activities. [Reproduced with permission from P. C. White
and P. W. Speiser, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Endocrine Reviews
2 1 ,245 (2000).]
capable of
de novo
cholesterol synthesis from acetate.
Cholesterol either is stored as a fatty acid ester or is imme-
diately utilized in steroidogenesis. The esterified choles-
terol is tapped when the cell is stimulated by the acti-
vation of cholesterolesterase, a cytoplasmic enzyme that
catalyzes the hydrolysis of cholesteryl esters to free
cholesterol and fatty acid. The steroidogenic pathway be-
gins in the mitochondria. The unesterified cholesterol is
transported from the cytosol to the matrix side of the mito-
chondrial membrane; this process is mediated by a 37-kDa
phosphoprotein known as stetoridogenic acute regula-
tory (StAR) protein. The importation of cholesterol from
cytosol to mitochondria is the rate-limiting step in the
steroidogenesis. Trophic stimuli such as ACTH in zona
fasciculata and zona reticularis and elevated cytosolic
Ca2+ in zona glomerulosa cause increased synthesis of
the StAR protein within minutes. Other proteins in ad-
dition to StAR are also involved in cholesterol transfer
across the mitochondrial membrane.
A number of enzymes in the steroidogenic path-
way are cytochrome P-450 proteins that require mole-
cular oxygen and NADPH (Chapter 14). These enzymes
catalyze the clevage of carbon-carbon bonds and hy-
droxylation reactions. The P-450 enzymes are distin-
guished by specific notations. For example, CYPI 1A
(also known as cholesterol desmolase, side chain clevage
enzyme, P450scc) is a mitochiondrial enzyme and cat-
alyzes the conversion of cholesterol (a C
2 7
compound) to
pregenolone (a C
steroid). CYP21 refers to the hydro-
xylase that catalyzes the hydroxyation at carbon 21. The
pathways of steroidogenesis are shown in Figure 30-2.
A true steroidogenic cell is equipped with the enzyme
A, which catalyzes the initial step of steroidoge-
nesis; the conversion of cholesterol to the steroid inter-
mediate, pregnenolone. CYPI 1A catalyzes the hydrox-
ylation of carbons
2 0
2 2
of cholesterol, followed
by the cleavage of the bond between these two hydrox-
ylated carbons. The resultant steroid, pregnenolone, is
2 1
-carbon derivative of cholesterol with a two-carbon
remnant side chain. It retains the A
configuration and
the 3/1-hydroxyI group of cholesterol, and is lacking in
biological activity; however, it is the universal intermedi-
ate in all steroid hormone synthesis. Because mitochon-
dria have no enzyme that recognizes pregnenolone as a
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