BIOCHEMISTRY - L. Stryer - 1984

VOLUME 3

PART V. MOLECULAR PHYSIOLOGY

CHAPTER 35. HORMONE ACTION

35.14. Several Peptide Hormones Are Formed by the Cleavage of Pro-opiomelanocortin

Although β-endorphin was discovered relatively recently, its Amino Acid Sequence turned out to be familiar. Indeed, β-endorphin shares the same sequence as the C-terminal region of β-lipotropin, a hormone isolated from the Pituitary Gland by Chou Li. In vivo, β-endorphin is generated through the proteolytic Cleavage of β-lipotropin stored in secretory granules. Subsequently, an even larger protein encompassing the sequences of both β-lipotropin and corticotropin was discovered. This prohormone (with a mass of 29 kDa) was named pro-opiomelanocortin because it serves as the precursor for an opiate hormone and corticotropin (Fig. 35.18). Corticotropin (also known as adrenocorticotropic hormone or ACTH) promotes the growth of the adrenal cortex and stimulates the synthesis of a variety of Steroid Hormones in this tissue. Two melanocyte-stimulating hormones (MSHs) are derived from pro-opiomelanocortin. One of them, α-MSH, is a fragment of corticotropin, whereas the other, β-MSH, is formed from β-lipotropin (Fig. 35.18). It is also possible that the N-terminal half of pro-opiomelanocortin serves as a source for Other Hormones as well. From the foregoing, it is clear that Peptide Hormones are generated from pro-opiomelanocortin as if from a horn of plenty. This prohormone consists of four homologous regions that presumably arose through successive Gene duplications.

Class="center">Fig. 35.18. Pro-opiomelanocortin is the biosynthetic precursor of several peptide hormones

The junction sites between prospective active hormones in pro-opiomelanocortin contain pairs of basic residues (Lys-Arg, Arg-Arg, or Lys-Lys). It is worth emphasizing that the BOUNDARIES OF THE C-peptide in proinsulin (see Fig. 35.11) and in proparathyroid hormone are also marked by pairs of basic residues. Evidently, these pairs of basic residues in various prohormones serve as the specific markers indicating where subsequent cleavage should take place.

35.15. Prostaglandins Are Modulators of Hormone Action

Let us now turn to Prostaglandins, a group of Fatty acids that influence A wide variety of physiological processes. These compounds were discovered in the 1930s but attracted widespread attention only recently, largely due to the pioneering work of Sune Bergström. Prostaglandins are 20-carbon fatty acids containing a 5-carbon ring. The main classes of prostaglandins are designated as PGA, PGB, PGE, and PGF, with a subscript indicating the number of carbon-carbon double bonds in the hydrocarbon chain (outside the ring). Prostaglandins do not appear to be classical hormones themselves, but rather modulate the Action of Hormones. Typically, they alter The activity of the very Cells in which they were synthesized. The Nature of prostaglandin action depends on The Cell type, which distinguishes them from hormones that have uniquely defined effects.

The MECHANISM OF ACTION of PGE₁ on fat mobilization in adipose tissue has been studied in detail. Hormones such as epinephrine, Glucagon, corticotropin, and thyrotropin stimulate lipolysis in these cells. PGE₁ at a concentration of 10^-8 M is a potent inhibitor of their lipolytic effect. Closely related to this is the fact that PGE₁ prevents the elevation of cAMP concentration induced by these hormones. However, PGE₁ does not inhibit lipolysis caused by The addition of dibutyryl-cAMP. Consequently, PGE₁ inhibits adenylate cyclase in adipose tissue cells. In other cell types, The Effect of prostaglandins on cAMP levels may be the opposite.

Fig. 35.19. Structures of several prostaglandins

The molecular basis for many effects of prostaglandins is still not fully understood. Physiologically, prostaglandins enhance inflammatory processes, regulate Blood flow to specific Organs, control Ion transport across certain membranes, and modulate synaptic transmission. Prostaglandins are of great clinical interest. For instance, they are believed to play a role in parturition; an infusion of PGE₂ induces labor within a few hours. Prostaglandins could potentially be used as contraceptives; it has been shown that PGF_2a decreases the se

cretion of progesterone, a hormone essential for the implantation of a fertilized egg in the Uterus.

35.16. Prostaglandins Are Formed from Unsaturated Fatty Acids

Prostaglandins are synthesized in membranes from C₂₀ fatty acids containing at least three double bonds. Mammals obtain these Unsaturated fatty acids from their diet (Section 17.23). Prostaglandin precursors are released from membrane Phospholipids through the action of phospholipases. The Biosynthesis of PGE₁, for example, begins with cis-∆⁸, ∆¹¹, ∆¹⁴-eicosatrienoate. The formation of the cyclopentane ring and the incorporation of three oxygen atoms are catalyzed by prostaglandin synthase (also called prostaglandin cyclooxygenase). As a priori expected, molecular oxygen serves as the source for all three oxygen atoms (Fig. 35.20). The heme-containing dioxygenase enzyme that catalyzes these reactions is associated with the smooth Endoplasmic reticulum.

Fig. 35.20. Synthesis of PGE₁ from cis-∆⁸, ∆¹¹, ∆¹⁴-eicosatrienoate

As John Vane demonstrated, aspirin inhibits prostaglandin biosynthesis by inactivating prostaglandin synthases. The reason for the suppression of this enzyme's activity by aspirin (acetylsalicylate) is that it acetylates the N-terminal amino group of one of the prostaglandin synthase subunits (Fig. 35.21). Prostaglandins promote inflammation, whereas aspirin suppresses it. This pharmacological effect of aspirin is apparently due to its inhibition of prostaglandin biosynthesis.

Fig. 35.21. Inactivation of prostaglandin synthase by aspirin