Steroid hormoneFrom the chemical standpoint, hormones can generally be divided into three types: The basic units of proteins and peptides breakfown amino acids, east german shepherd puppies steroids contain the gonane structure. Steroid hormone breakdown are relatively large molecules and are water breakdonw, whereas steroids are small molecules and are generally soluble in organic solvents. Peptides are somewhere in between these two classes of hormones with respect to molecular weight and solubility. The basic structure of steroids, gonane cyclopentanoperhydrophenanthrenehas 17 carbons which are arranged as three six-member carbon rings to which a five-member carbon ring is attached Fig. Each carbon has one or two hydrogens attached.
Steroids: Structure & Function - Video & Lesson Transcript | jmhw.info
Cholesterol is a precursor for other important steroid molecules: As polar derivatives of cholesterol, bile salts are highly effective detergents because they contain both polar and nonpolar regions. Bile salts are synthesized in the liver, stored and concentrated in the gall bladder, and then released into the small intestine. Bile salts, the major constituent of bile, solubilize dietary lipids Section Solubilization increases in the effective surface area of lipids with two consequences: Bile salts are also the major breakdown products of cholesterol.
Cholesterol is converted into trihydroxycoprostanoate and then into cholyl CoA , the activated intermediate in the synthesis of most bile salts Figure The activated carboxyl carbon of cholyl CoA then reacts with the amino group of glycine to form glycocholate or it reacts with the amino group of taurine H 2 NCH 2 CH 2 SO 3 - , derived from cysteine, to form taurocholate.
Glycocholate is the major bile salt. Synthesis of Bile Salts. Pathways for the formation of bile salts from cholesterol. Cholesterol is the precursor of the five major classes of steroid hormones: These hormones are powerful signal molecules that regulate a host of organismal functions. Progesterone, a progestagen, prepares the lining of the uterus for implantation of an ovum. Progesterone is also essential for the maintenance of pregnancy. Androgens of male secondary sex characteristics, whereas estrogens such as estrone are required for the development of female secondary sex characteristics.
Estrogens, along with progesterone, also participate in the ovarian cycle. Glucocorticoids such as cortisol promote gluconeogenesis and the formation of glycogen, enhance the degradation of fat and protein, and inhibit the inflammatory response.
They enable animals to respond to stress—indeed, the absence of glucocorticoids can be fatal. The major sites of synthesis of these classes of hormones are the corpus luteum, for progestagens; the ovaries, for estrogens; the testes, for androgens; and the adrenal cortex, for glucocorticoids and mineralocorticoids.
Steroid hormones bind to and activate receptor molecules that serve as transcription factors to regulate gene expression Section These small, relatively similar molecules are able to have greatly differing effects because the slight structural differences among them allow interactions with specific receptor molecules. Carbon atoms in steroids are numbered as shown for cholesterol in Figure The rings in steroids are denoted by the letters A , B, C , and D.
Cholesterol contains two angular methyl groups: The C and C methyl groups of cholesterol lie above the plane containing the four rings. The numbering scheme for the carbon atoms in cholesterol and other steroids. The absence of a Greek letter for the C-5 hydrogen atom on the steroid nucleus implies a trans fusion.
Thus, a cis fusion is characteristic of the bile salts, whereas a trans fusion is characteristic of all steroid hormones that possess a hydrogen atom at C A trans fusion yields a nearly planar structure, whereas a cis fusion gives a buckled structure. Hydroxylation reactions play a very important role in the synthesis of cholesterol from squalene and in the conversion of cholesterol into steroid hormones and bile salts. The oxygen atom of the incorporated hydroxyl group comes from O 2 rather than from H 2 O.
While one oxygen atom of the O 2 molecule goes into the substrate, the other is reduced to water. The enzymes catalyzing these reactions are called monooxygenases or mixed-function oxygenases. Recall that a monooxygenase also participates in the hydroxylation of aromatic amino acids Section Hydroxylation requires the activation of oxygen. In the synthesis of steroid hormones and bile salts, activation is accomplished by a cytochrome P, a family of cytochromes that absorb light maximally at nm when complexed in vitro with exogenous carbon monoxide.
Because the hydroxylation reactions promoted by P enzymes are oxidation reactions, it is at first glance surprising that they also consume the reductant NADPH.
NADPH transfers its high-potential electrons to a flavoprotein, which transfers them, one at a time, to adrenodoxin, a nonheme iron protein. Without the addition of this electron, P will not bind oxygen. Recall that only the ferrous form of hemoglobin binds oxygen Section The binding of O 2 to the heme is followed by the acceptance of a second electron from adrenodoxin. The acceptance of this second electron leads to cleavage of the O—O bond.
One of the oxygen atoms is then protonated and released as water. This transient free radical captures the OH group from the iron atom to form ROH, the hydroxylated product, returning the iron atom to the ferric state.
These enzyme-bind O 2 and use one oxygen atom to hydroxylate their substrates. The cytochrome P system, which in mammals is located primarily in the endoplasmic reticulum of the liver and small intestine, is also important in the detoxification of foreign substances xenobiotic compounds by oxidative metabolism.
For example, the hydroxylation of phenobarbital, a barbiturate, increases its solubility and facilitates its excretion. Likewise, polycyclic aromatic hydrocarbons are hydroxylated by P, providing sites for conjugation with highly polar units e.
One of the most relevant functions of the cytochrome P system to human beings is its role in drug metabolism. Drugs such as caffeine and ibuprofen are oxidatively metabolized by these monooxygenases. Indeed, the duration of action of many medications depends on their rate of inactivation by the P system.
Despite its general protective role in the removal of foreign chemicals, the action of the P system is not always beneficial. Some of the most powerful carcinogens are generated from harmless compounds by the P system in vivo in the process of metabolic activation. In plants, the cytochrome P system plays a role in the synthesis of toxic compounds as well as the pigments of flowers.
The cytochrome P system is a ubiquitous superfamily of monooxygenases that is present in plants, animals, and prokaryotes. The human genome encodes more than 50 members of the family, whereas the genome of the plant Arabidopsis encodes more than members.
All members of this large family arose by gene duplication followed by subsequent divergence that generated a range of substrate specificity. Indeed, the specificity of these enzymes is encoded in delimited regions of the primary structure, and the substrate specificity of closely related members is often defined by a few critical residues or even a single amino acid.
Steroid hormones contain 21 or fewer carbon atoms, whereas cholesterol contains Thus, the first stage in the synthesis of steroid hormones is the removal of a six-carbon unit from the side chain of cholesterol to form pregnenolone. The side chain of cholesterol is hydroxylated at C and then at C, and the bond between these carbon atoms is subsequently cleaved by desmolase.
Adrenocorticotropic hormone ACTH, or corticotropin , a polypeptide synthesized by the anterior pituitary gland, stimulates the conversion of cholesterol into pregnenolone, the precursor of all steroid hormones. Progesterone is synthesized from pregnenolone in two steps.
Cortisol, the major glucocorticoid, is synthesized from progesterone by hydroxylations at C , C, and C; C must be hydroxylated before C is, whereas C can be hydroxylated at any stage. The enzymes catalyzing these hydroxylations are highly specific, as shown by some inherited disorders.
The initial step in the synthesis of aldosterone, the major mineralocorticoid, is the hydroxylation of progesterone at C The resulting deoxycorticosterone is hydroxylated at C The oxidation of the C angular methyl group to an aldehyde then yields aldosterone.
Pathways for the Formation of Progesterone, Cortisol, and Aldosterone. Androgens and estrogens also are synthesized from pregnenolone through the intermediate progesterone. Androgens contain 19 carbon atoms. The synthesis of androgens Figure The side chain consisting of C and C is then cleaved to yield androstenedione, an androgen.
Testosterone, another androgen, is formed by the reduction of the keto group of androstenedione. Testosterone, through its actions in the brain, is paramount in the development of male sexual behavior.
It is also important for maintenance of the testes and development of muscle mass. Owing to the latter activity, testosterone is referred to as an anabolic steroid. Testosterone is reduced by 5a-reductase to yield dihydrotestosterone DHT , a powerful embryonic androgen that instigates the development and differentiation of the male phenotype.
Estrogens are synthesized from androgens by the loss of the C angular methyl group and the formation of an aromatic A ring. Estrone, an estrogen, is derived from androstenedione, whereas estradiol, another estrogen, is formed from testosterone. Cholesterol is also the precursor of vitamin D, which plays an essential role in the control of calcium and phosphorus metabolism. Vitamin D 3 cholecalciferol is converted into calcitriol 1,dihydroxycholecalciferol , the active hormone, by hydroxylation reactions in the liver and kidneys.
Although not a steroid, vitamin D acts in an analogous fashion. It binds to a receptor, structurally similar to the steroid receptors, to form a complex that functions as a transcription factor, regulating gene expression.
The pathway for the conversion of 7-dehydrocholesterol into vitamin D 3 and then into calcitriol, the active hormone. Vitamin D deficiency in childhood produces rickets, a disease characterized by inadequate calcification of cartilage and bone. Furthermore, their diets provided little vitamin D, because most naturally occurring foods have a low content of this vitamin. Fish-liver oils are a notable exception. Cod-liver oil, abhorred by generations of children because of its unpleasant taste, was used in the past as a rich source of vitamin D.
Today, the most reliable dietary sources of vitamin D are fortified foods. The recommended daily intake of vitamin D is international units, irrespective of age. In adults, vitamin D deficiency leads to softening and weakening of bones, a condition called osteomalacia. The occurrence of osteomalacia in Bedouin Arab women who are clothed so that only their eyes are exposed to sunlight is a striking reminder that vitamin D is needed by adults as well as by children.
Before this chapter ends, we will revisit isopentenyl pyrophosphate, the activated precursor of cholesterol. The combination of isopentenyl pyrophosphate C 5 units to form squalene C 30 exemplifies a fundamental mechanism for the assembly of carbon skeletons of biomolecules.
A remarkable array of compounds is formed from isopentenyl pyrophosphate, the basic five-carbon building block. The fragrances of many plants arise from volatile C 10 and C 15 compounds, which are called terpenes. For example, myrcene C 10 H 16 from bay leaves consists of two isoprene units, as does limonene C 10 H 15 from lemon oil Figure