Cortisol Biosynthesis Pathway
by Benjamin Bunting BA(Hons) PGCert
Written by Ben Bunting: BA, PGCert. (Sport & Exercise Nutrition) // British Army Physical Training Instructor // S&C Coach.
The cortisol biosynthesis pathway involves four different enzymes that are crucial in regulating cortisol levels in the body. These enzymes are HSD3B2, ACTH, gluconeogenesis, and superoxide dismutase. Each has a specific role in cortisol biosynthesis, so we need to know how these enzymes work together to produce cortisol.
Cortisol biosynthesis occurs in several organs in the body, including the adrenal cortex and the testes. The hormones ACTH and LH are responsible for increasing expression of genes such as StAR. LH stimulates steroid biosynthesis by increasing the expression of the steroidogenic acute regulatory protein (StAR). The StAR gene is found in several species, and is highly conserved in humans, mice, and flies.
The StAR gene product, a prototypical member of the START domain family, regulates the transfer of cholesterol from the mitochondria to the steroid biosynthesis pathway. The START domain in StAR forms a pocket in the protein that binds single cholesterol molecules and delivers them to the P450scc. StAR's closest homolog is the protein MLN64 (STARD3). StAR is a mitochondrial protein that is rapidly synthesized in response to steroid hormone stimulation. This protein is found in the adrenal cortex, theca cells in the ovary, and Leydig cells in the testis.
The cortisol biosynthesis pathway is responsible for the production of glucocorticoid hormones. These hormones are important regulators of many physiological processes. CYP17A1 and HSD3B2 are two key enzymes involved in this pathway. They catalyze the 17a hydroxylation of progesterone and pregnenolone.
Both P4 and 17OHP4 are converted to corticosterone by enzymes that are found in the same tissues. The pathways are activated when the adrenal glands are stimulated. When a person experiences a stressful event or is under stress, he or she experiences an increase in P4, which in turn leads to the production of corticosterone. Throughout a person's life, the levels of corticosterone may fluctuate and are regulated by hormone levels.
A gene variant that impairs cortisol biosynthesis causes congenital adrenal hyperplasia (CAH). It is an inherited condition in which the adrenal cortex develops in an overly large size.
Gluconeogenesis is a vital step in the synthesis of cortisol and other hormones. It produces glucose by converting fatty acids to glycerol. However, this step is complicated by other processes. For example, adipocytes can only generate gluconeogenesis when they are provided with the glycerol backbone. This glycerol backbone must first be converted to glycerol-3-phosphate by a glycerol kinase enzyme in the liver.
The next step in this pathway is the reduction of OAA to malate by mitochondria. This step requires NADH, which accumulates in the mitochondrion as the energy charge increases. Gluconeogenesis proceeds to the cytosol, where it is oxidized by the cytosolic MDH. NADH is then used in the subsequent glyceraldehyde-3-phosphate dehydrogenase reaction.
Superoxide dismutase (SOD) is a cellular enzyme that reduces superoxide to less harmful species. The SOD enzyme is a polypeptide that consists of a manganese cation in its reactive center. It is found in mitochondria, cytoplasm, and extracellular regions of cells.
It is believed that SOD3 helps maintain healthy cell function by reducing the amount of superoxide, the primary cellular reactive oxygen species. The enzyme helps the body break down harmful oxygen molecules in cells and may protect against tissue damage. There are several superoxide dismutase products on the market, some derived from cows, melons, and labs, while others are synthesized from synthetic compounds. Some of these products are used to treat osteoarthritis, stress, and other health problems.
This study was designed to investigate whether Superoxide dismutase is associated with the biosynthesis of cortisol in animals subjected to chronic stress or supplementation with resveratrol. Blood samples were collected before and after treatments. Blood samples were obtained from animals by breaking the venous plexus in the ocular orbit with a heparinized capillary. The animals were then anesthetized with diethyl ether and sacrificed by cardiac puncture. The blood samples were then placed in vacutainer tubes and centrifuged at 1,300 x g for 5 minutes. The plasma was then stored at -20 degrees C until processing.
StAR-dependent copper enzymes
Cortisol has a remarkable capacity to induce the activity of many copper enzymes, often up to 50%. Among these enzymes is lysyl oxidase, which is crucial for the crosslinking of collagen and elastin. Other copper enzymes that are induced by cortisol include superoxide dismutase, which can be helpful in fighting bacteria.
This study analyzed the expression of genes involved in cortisol synthesis in mice. It found that mRNA abundance increased along with cortisol levels, and that mRNA abundance correlated with protein function. Furthermore, mRNA levels were significantly higher at 49 and 97 hpf than at 25 hpf.
Cortisol Biosynthesis Pathway Conclusion
The Cortisol Biosynthesis Pathway regulates several physiological processes in the body, including the production of steroid hormones. The enzymes involved in this pathway use the electron transfer protein ferredoxin to generate steroid hormones. This enzyme is required in several steps in the pathway, including the production of cortisol. The deficiency of 21-hydroxylase is the most common cause of CAH. Other factors contributing to the development of CAH include a defect in a cholesterol transport protein.
Cortisol and corticosterone are produced in the body using the same enzymes, which are similar in structure. The enzymes responsible for the conversion of P4 and 17OHP4 to corticosterone are CYP17A1 and HSD3B2. During adrenal stimulation, the pathway is activated, and an increase in P4 leads to the production of corticosterone. However, only a small portion of the P4 is converted into cortisol.
TGF1 inhibits the steroidogenic pathway upstream of 11-hydroxylation, inhibiting the conversion of exogenous steroid precursors into cortisol. These precursors include 25-OH cholesterol, 17-hydroxypregnenolone, and 17-hydroxyprogesterone. In a study using the NCI-H295R cells, TGF1 inhibited cortisol production by 90 percent.
In one study, researchers examined intratumoral steroid biosynthesis in a tumor containing CPA and adjacent normal adrenal tissue. They found significant intratumoral steroid biosynthesis. They then quantified the steroids using LC-MS/MS. The results showed that CPA has increased steroid levels compared with AdjN and OCS. These results support the idea that CPA can be used to define intra-tissue steroid profiles.