Inactivation and Degradation of Hormones

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Figure 20.14 Cellular mechanisms for T3 and T4 release into the bloodstream. Iodide trapping at basal membrane of thyroid epithelium concentrates iodide approximately 30­fold. Secretion of T3 and T4 into bloodstream requires endocytosis of thyroglobulin and subsequent proteolysis. DIT and MIT are deiodinated and the released iodide ions are reutilized for hormone synthesis.
20.6— Inactivation and Degradation of Hormones
Most polypeptide hormones are degraded to amino acids by hydrolysis, which presumably occurs in the lysosome. Partial hydrolysis by proteinases is a principal pathway for degradation. Certain hormones, however, contain modified amino acids; for example, among the hypothalamic releasing hormones, the N­terminal amino acid can be cycloglutamic acid (or pyroglutamic acid) (Table 20.4) and a C­terminal amino acid amide. Some of the releasing hormones
TABLE 20.4 Hypothalamic Releasing Hormones Containing an N­Terminal Pyroglutamate, a a C­Terminal Amino Acid Amide, or Both
Hormone
Sequenceb
Thyrotropin­releasing hormone pGlu­H­Pro­NH
2
(TRH)
Gonadotropin­releasing hormone (GnRH)
pGlu­HWSYGLRP­Gly­NH2
Corticotropin­releasing hormone (CRH)
SQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDI­Ala­NH2
Somatocrinin (GRH)
YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERG­ARAR­ Leu­
NH2
a
The pyroglutamate structure is
b Single­letter abbreviations used for amino acids: Ala, A; Arg, R; Asn, N; Asp, D; Cys, C; Glu, E, Gln, Q; Gly, G; His, H; Ile, I; Leu, L; Lys, K; Met, M; Phe, F; Pro, P; Ser, S; Thr, T; Trp, W; Tyr, Y; Val, V.
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that have either or both of these amino acid derivatives are listed in Table 20.4. Apparently, breakage of the cyclic glutamate ring or cleavage of the C­terminal amide can lead to inactivation of many of these hormones and such enzymic activities have been reported in blood. This activity probably accounts, in part, for the short half­
life of many of these hormones.
TABLE 20.5 Examples of Hormones Containing a Cystine Disulfide Bridge Structure
Hormone
Sequencea
Somatostatin
Oxytocin
Arginine vasopressin
a
Letters refer to single­letter amino acid abbreviations (see Table 20.4)
Some hormones contain a ring structure joined by a cystine disulfide bond. A few examples are given in Table 20.5. Peptide hormones, such as those shown in Table 20.5, may be degraded initially by the random action of cystine aminopeptidase and glutathione transhydrogenase as shown in Figure 20.15. Alternatively, as has been suggested in the case of oxytocin, the peptide may be broken down through partial proteolysis to shorter peptides, some of which may have hormonal actions on their own. Maturation of prohormones in many cases involves proteolysis, which may be considered as a degradation process in the sense that the prohormone is degraded to active forms (e.g., Figure 20.5), although degradation is usually thought of as the reduction of active peptides to inactive ones.
Figure 20.15 Degradation of posterior pituitary hormones. Oxytocin transhydrogenase is similar to degrading enzymes for insulin; presumably, these enzymes also degrade vasopressin. Redrawn from Norman, A. W., and Litwack, G. Hormones. New York: Academic Press, 1987, p. 167.