Essential Endocrinology and Diabetes. Richard I. G. Holt
Box 2.3 Role of post‐translational modifications
Post‐translational modifications mean:
Great diversity of hormone action can be generated from a more limited range of protein‐coding genes
The synthesizing cell is protected from being overwhelmed by its own hormone action
Storage and secretion of peptide hormones
Newly synthesized peptide hormone is stored within the cell in small vesicles or secretory granules. Movement of these vesicles to a position near the cell membrane is influenced by two types of filamentous structure: microtubules and microfilaments (Figure 2.3a). Consequently, the secretion of stored hormone tends to be rapid but only occurs after appropriate stimulation of the cell. Whether this is hormonal, neuronal or nutritional, it usually involves a change in cell membrane permeability to calcium ions. These divalent metal ions are required for interaction between the vesicle and plasma membrane, and for the activation of enzymes, microfilaments and microtubules. The secretory process is called ‘exocytosis’ (Figure 2.3a). The membrane of the storage granule fuses with the cell membrane at the same time as vesicular endopeptidases are activated. The active hormone is expelled into the extracellular space from where it enters the bloodstream. The vesicle membrane is then recycled within the cell.
Synthesizing a hormone derived from amino acids or cholesterol
In addition to peptides or proteins, hormones can also be synthesized by sequential enzymatic modification of either the amino acids tyrosine and tryptophan, or cholesterol.
Enzyme action and cascades
Enzymes can be divided into classes according to the reactions they catalyze (Table 2.1). In endocrinology, they frequently operate in cascades where the product of one reaction serves as the substrate for the next. The most simplistic representation of an enzymatic reaction is a physical interaction between the substrate and the enzyme at the latter’s ‘active site’. This proximity catalyzes a molecular modification of the substrate into the product. The product has less affinity for the active site and is released. Other macromolecules can also bind to the enzyme outside the active site and function as co‐factors, adding more complex regulation to the biochemical reaction.
Table 2.1 Definition and classification of enzymes
| Definition | ||
| An enzyme is a biological macromolecule – most frequently a protein – that catalyzes a biochemical reaction | ||
| Catalysis increases the rate of reaction, e.g. the disappearance of substrate and generation of product | ||
| Enzyme action is critical for the synthesis of hormones derived from amino acids and cholesterol | ||
| Classification | ||
| Enzyme | Catalytic function | Example (and relevance) |
| Hydrolases | Cleavage of a bond by the addition of water | Cytochrome P450 11A1/cholesterol side‐chain cleavage (CYP11A1; an early step in steroid hormone biosynthesis) |
| Lyases | Removal of a group to form a double bond or addition of a group to a double bond | Cytochrome P450 17α‐hydroxylase/17–20 lyase (CYP17A1; step in the synthesis of steroid hormones other than aldosterone) |
| Isomerases | Intramolecular rearrangements | 3β‐Hydroxysteroid dehydrogenase/δ‐4,5‐isomerase isoforms (HSD3B; a step in the synthesis of many major steroid hormones) |
| Oxidoreductase | Oxidation and reduction | 11β‐Hydroxysteroid dehydrogenase isoforms (HSD11B; inter‐conversion of cortisol and cortisone) |
| Ligases or synthases | Join two molecules together | Thyroid peroxidase (TPO; a step in the synthesis of thyroid hormone) |
| Transferases | Transfer of a molecular group from substrate to product | Phenolethanolamine N‐methyl transferase (PNMT; conversion of norepinephrine to epinephrine) |
Patients can present with many endocrine syndromes because of loss of enzyme function. For instance, gene mutation might lead to substitution of an amino acid at a key position of an enzyme’s active site. The three‐dimensional structure might be affected so significantly that the substrate is no longer converted to product. In the enzyme cascade that synthesizes cortisol, such mutations can cause various forms of congenital adrenal hyperplasia (CAH) (Chapter 6). Understanding the biochemical cascade allows accurate diagnosis as the product is lacking while the substrate builds up and can be measured, e.g. by immunoassay or mass spectrometry (Chapter 4).
Synthesizing hormones derived from amino acids
The amino acid tyrosine can be modified by sequential enzyme action to give rise to several hormones (Box 2.4). The precise synthetic pathways for dopamine and catecholamines are described in Chapter 6 (Figure 6.11) and for thyroid hormones in Chapter 8 (Figure 8.4). Melatonin is important in circadian rhythms and is linked to type 2 diabetes. It is generated from the amino acid tryptophan via synthesis of the neurotransmitter, serotonin.
Box 2.4 Hormones derived from tyrosine
Thyroid hormones: sequential addition of iodine and coupling of two tyrosines together (Chapter 8)
Adrenomedullary hormones: hydroxylation steps and decarboxylation to form dopamine and catecholamines (Chapter 6)
Hypothalamic dopamine formed by hydroxylation and decarboxylation (Chapter 5)
Synthesizing hormones derived from cholesterol
Steroid