Second Assignment: The Structure of ACTH, and its precurser Proopiomelanocortin!

Adrenocorticotropic hormone (ACTH) is a 39 amino acid long peptide hormone that is actually the product of post-translational processing. It's precursor is a prohormone known as POMC or Proopiomelanocortin. Proopiomelanocortin is 241 amino acids long after the dignal peptide has been removed, and can be cleaved into a variety of different hormone messengers (Tanaka, 2003). ACTH is cleaved from POMC in the rough endoplasmic reticulum and the golgi apparatus by enzymes known as prohormone convertases. PC1 cleaves the ACTH from an already cleaved ABI product during post-translational processing (Tanaka, 2003). Since ACTH is cleaved from another peptide, it is not directly coded for by a gene. Therefore, in this post we will be looking at the amino acid sequence of POMC as coded for by the DNA of several species of frogs and toads.

 

Figure 1:  This image illustrates the action of PC1 cleaving ACTH from the  prohormone POMC. Taken from (Tanaka, 2003). Along with the 2D structure of ACTH. Taken from http://pubchem.ncbi.nlm.nih.gov/image/imagefly.cgi?cid=16132265&width=300&height=300.

 ACTH is only 39 amino acids long, and as such, has a secondary structure of a single alpha helix (Brunton et al. 2013). Amino acids 1-10 are responsible for binding and signalling the MC2R receptor in the Zonae Fasciculata of the adrenal medulla (Gao & Wong 1998). This area contains many serine acids which help to create hydrogen bonds with the receptor. Once bound, the receptor changes conformation and activates a G-protein linked secondary messenger pathway eventually leading to the production and release of glucocorticoids. 

Figure 2: This figure shows the alignment for the Marshfrog (Accession number M62770.1), African Clawed Frog ( Accession number: NM_001087369.1) and the oriental fire bellied toad (Accession number AY692246.1), as well as the approximate position of ACTH in the POMC prohormone.

KEY: " * " (Asterisk) indicates the position of a single fully conserved residue, " : " (Colon) indicates conservation of groups with strongly similar properties. " . " (Period) indicates conservation of groups with weakly similar properties.


As we can see from the above alignment, the section of POMC corresponding to ACTH is highly conserved, showing that the sequence is functionally very important. We can see that specifically, the serine residues at the beginning of the peptide are conserved, due to their function in binding of the MC2R receptor.

 Figure 3: This figure shows the Percent Identity Matrix for the POMC alignments of the Marsh Frog, African-clawed Frog, and the Oriental fire-bellied toad.

  From the Percent Identity Matrix, we can see that ~ 70-75% of amino acid sequence is conserved between each genus of toad and frog. All of these species are fairly analagous, and even though they are extremely geographically seperated, their hormonal structure is still similar.

References:
 
1) Shigeyasu Tanaka. (2003). Comparative Aspects of Intracellular Proteolytic processing of Peptide Hormone Precursers: Studies of Proopiomelanocortin Processing. Zoological Science. 20. P. 1183-1198
2) http://pubchem.ncbi.nlm.nih.gov/image/imagefly.cgi?cid=16132265&width=300&height=300
3) Brunton, Lawrence L., Lazo, John S., & Keith L. Parker. (2013). Goodman and Gilman's The Pharmological Basis for Therpeutics. 12th Ed. McGraw and Hill. New York. 
4)Gao, Xinfeng., & Tuck C. Wong. (1998). Studied of the Binding and Structure of Adrenocorticotropin Peptides in Membrane Mimics by NMR Spectroscopy and Pulsed-Field Gradient Diffusion. BioPhysical Journal. 74(11). P. 1871-1888

First Assignment: An introduction to Adrenocorticotropic hormone!

Adrenocorticotropic hormone (ACTH) is a peptide hormone. It is created from a 266 amino acid precursor known as proopiomelanocortin (POMC). ACTH is cleaved from POMC into a 39 amino acid long protein (Schlomo Melmed, 2011). This hormone is created in the adenohypophysus, or anterior pituitary, by corticotroph cells. ACTH can be detected in mammals such as dogs as early as the eighth week of the fetal stage, as Rathke's diverticulum (the predecessor of the anterior pituitary) extends to merge with the diencephalon (Schlomo Melmed, 2011).

As the term "Adrenocortico" suggests, ACTH is highly involved in mediation of function for the cortex of the adrenal glands. ACTH is released from the anterior pituitary into the blood where it stimulates the release of glucocorticoids such as the steroid hormone cortisol. Glucocorticoids are highly involved in digestion, the stress response, and physiological development (Bundgaard & Rehfeld, 2010). Thus, regulation for the release of ACTH is extremely important. ACTH works on a 24 hour circadian rhythm and peaks in the morning when it is time for the body to become awake and alert. The release of ACTH is stimulated by the release of corticotropin releasing hormone (CRH) from the hypothalamus. When ACTH is released into the blood, it binds to receptors of secretory cells in the adrenal cortex and triggers a G protein linked secondary messenger pathway. Glucocorticoids such as cortisol are then released into the blood stream where they cause gluconeogenesis from the liver. Glycogen is broken down and released as glucose into the blood stream where it provides energy for the body. Other functions of the glucocorticoids include moderating the metabolism of proteins, fat and carbohydrates, as well as controlling leukocyte production and inflammation during the immune response (Bundgaard and Rehfeld, 2010). The release of ACTH is mediated by the concentration of glucose and cortisol in the bloodstream. The hypothalamus registers when cortisol levels are peaking and thus releases less CRH, which in turn causes the stymied release of ACTH from the adenohypophysis.

The importance of glucocorticoids can be seen by the symptoms of patients who suffer from Cushing Syndrome, also known as hyperadrenocorticism. This condition is caused by an excess release of CRH in the hypothalamus or cortisol from the adrenal glands into the blood stream. The disease is often caused by a hormone secreting tumor in the glucocorticoid pathway (Constantine A. Stratikis, 2012). Since cortisol is highly involved in the metabolic production of fats and proteins, cushings syndrome causes rapid weight gain.

ACTH plays an extremely integral role in the metabolic pathway of the body. We still do not know many of its functions. Research has proven that synthetic ACTH can even be used to treat mild cases of epilepsy (Croiset & De Weid, 1992). There is so much still to be discovered about metabolic hormones such as ACTH, which is why I chose it as my favorite hormone!

Figure 1: The CRH, ACTH, and Cortisol secretory pathway showing how cortisol levels and stresses affect secretion. Taken from http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/adrenal/feedback.gif

References:

1) Melmed, S. (2011). Adrenocorticotropin. In The Pituitary (Third ed., pp. 47-50). San Diego, California: Blackwell Science.
2) Croiset, G., & De Wied, D. (1992). ACTH: A structure-activity study on pilocarpine-induced epilepsy. European Journal of Pharmacology, 229(2-3), 211-216.
3) Rehfeld, J., & Bundgaard, J. (2010). ACTH: Cellular Peptide Hormone Synthesis and Secretory Pathways. In Cellular Peptide Hormone Synthesis and Secretory Pathways (pp. 70-88). New York, New York: Springer.
4) Stratakis, C. (2012). Cushing Syndrome in Pediatrics. Endocrinology and Metabolism Clinics of North America, 41(4), 793-803.
5) http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/adrenal/feedback.gif