Classification and Genetic Features
Peptide hormones exhibit enormous structural diversity. Based on molecular size, they are traditionally divided into two large groups:
- Short peptides. This group includes molecules with a small number of amino acid residues. A classic example is thyrotropin-releasing hormone (TRH), which is produced in the hypothalamus and consists of just a tripeptide.
- Glycoproteins. These are large, complex protein molecules containing a carbohydrate component. Most hormones secreted by the anterior pituitary gland belong to this class.
An interesting genetic feature of this group of substances is that functionally distinct hormones can be encoded by a single common gene. All information encoded in DNA is transcribed, and during translation, a single polypeptide chain is assembled, which is subsequently cleaved into separate functional blocks.
Processing Stages: From Preprohormone to Active Forms
The synthesis of peptide hormones never immediately yields an active substance. Ribosomes first produce a large molecule—the preprohormone. For it to become a functional regulator, limited proteolysis is required, taking place in several stages.
- Cleavage of the signal peptide. A specialized signal sequence (usually consisting of 26 amino acids) is located at the N-terminus of the molecule. Its primary task is to direct protein transport. Once this function is fulfilled, the peptide is removed by enzymes.
- Initial cleavage. The remaining polypeptide chain is cleaved into two large fragments. For example, adrenocorticotropic hormone (ACTH), consisting of 39 amino acids, and $\beta$-lipotropin ($\beta$-LPH), comprising 42 to 134 amino acids, are formed from a common precursor.
- Further tissue-specific proteolysis. This stage proceeds differently depending on the tissue where the hormone is located. For instance, in the anterior and intermediate lobes of the pituitary gland, the fate of the molecules diverges:
- ACTH yields $\alpha$-melanocyte-stimulating hormone ($\alpha$-MSH) and corticotropin-like intermediate lobe peptide (CLIP).
- From $\beta$-LPH, $\gamma$-LPH (the precursor of $\beta$-MSH) is formed first, along with $\beta$-endorphin, which is then sequentially cleaved into $\gamma$-endorphin and $\alpha$-endorphin.
Insulin Biosynthesis as a Classic Example
Let us examine the maturation process using insulin as an example, which demonstrates clear spatial organization of processing.
Synthesis in the Endoplasmic Reticulum (ER) The process begins when the signal peptide directs the growing amino acid chain directly into the lumen of the ER. Assembly of preproinsulin is completed there. Immediately thereafter, the signal sequence is cleaved, and the molecule is converted into proinsulin.
Processing in the Golgi Apparatus The proinsulin molecule, consisting of 86 amino acids, is transported to the Golgi apparatus. Here, specific proteases come into play. They excise a fragment from the central part of the molecule, resulting in two separate substances: insulin itself (51 amino acids) and the C-peptide (31 amino acids).
Storage and Secretion The finished molecules of insulin and C-peptide are packaged into secretory granules. It is important to note that they are present there in a strict equimolar ratio (1:1). For compact storage within mature granules, insulin assembles into dimers and hexamers. The hormone is released via exocytosis when granules fuse with the plasma membrane into the extracellular fluid. Upon entering the circulation, the oligomeric insulin complexes rapidly dissociate into active monomers.