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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

21

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

CYPI 1

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

and

2 2

of cholesterol, followed

by the cleavage of the bond between these two hydrox-

ylated carbons. The resultant steroid, pregnenolone, is

a

2 1

-carbon derivative of cholesterol with a two-carbon

remnant side chain. It retains the A

5

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