ACTH and Related Peptide Sequences

Definition
Adrenocorticotropic hormone (ACTH) or corticotropin is a hormone produced by the anterior pituitary gland that stimulates the adrenal cortex.

Related peptides
The six related peptides include smaller biologically active fragments (hormones) which are derived from a common precursor by differential processing of the pro-opiomelanocortin polyprotein (POMC) viz. ACTH, corticotrophin like intermediate lobe protein [CLIP], ß-endorphin, gamma-lipotropin [yLPH], met-encephalin and alpha-melanotropin [aMSH]1.

Discovery
The properties of ACTH were first investigated in the 1930s. In 1933, research groups headed by James Collip, Herbert Evans and Bemardo Houssay used pituitary extracts to stimulate the adrenal cortex. American biochemist Choh Hao Li was one of several scientists who isolated ACTH in 1943 and synthesized it in 1963.

Structural characteristics
ACTH has a molecular weight of 4541.3 K Da2. It is a straight-chain peptide molecule consisting of 39 amino. The first 24 and last 7 amino acids are identical and there are minor differences in amino acids 25 through 32. Only the first 20 amino acids are required for full activity, referred as active centre.

Mechanism of action
ACTH enters the systemic circulation and binds to specific high affinity receptors located on the surface of adrenal cortical cells and the skin. ACTH receptor is a seven membrane-spanning G-protein coupled receptor3, which upon ligand binding undergoes conformation changes that stimulate the enzyme adenylate cyclase, which leads to an increase in intracellular cAMP and subsequent activation of protein kinase A. The activation of protein kinase A ultimately results in stimulation of steroidogenesis.

Function
ACTH's principal function is to stimulate the cortex of the adrenal glands to secrete a group of steroid hormones called glucocorticoids, mineralocorticoids and androgens steroids. Glucocorticoid hormones control the body's use of sugar and also help regulate biological functions during stressful moments. It stimulates the conversion of cholesterol into pregnenolone, the precursor of all steroid hormones. It is used in the treatment of rheumatoid arthritis, ulcerative colitis, hepatitis and to relieve pain. They play a major role in memory processing, by facilitating essential protein synthesis at sites specific for the memory4.

References
1. Funkelstein L, Toneff T, Mosier C, Hwang SR, Beuschlein F, Lichtenauer UD, Reinheckel T, Peters C, Hook V (2008). Major role of cathepsin L for producing the peptide hormones ACTH, beta-endorphin, and alpha-MSH, illustrated by protease gene knockout and expression. J Biol Chem., 283(51):35652-35659.
2.Lee TH, Lerner AB, Buettner-Janusch V (1961). On the structure of human corticotropin (adrenocorticotropic hormone). J. Biol. Chem., 236:2970-2974.
3.Mountjoy KG, Robbins LS, Mortrud MT, Cone RD (1992). The cloning of a family of genes that encode the melanocortin receptors. Science, 257:248–1251
4.Flood JF, Jarvik ME, Bennett EL, Orme AE (1976). Effects of ACTH peptide fragments on memory formation. Pharmacol Biochem Behav., 5:41-51.