ACTH( 1-39) Peptide

Core functional domain: The N-terminal 1-24 amino acids are the receptor binding and activation core region, which can independently bind to the melanocortin 2 receptor (MC2R) and activate downstream signals, possessing complete biological activity; The C-terminus 25-39 is the regulatory region responsible for maintaining molecular stability, regulating metabolic rate in vivo, and enhancing receptor binding affinity.
Physical and chemical properties: soluble in water, dilute hydrochloric acid, and phosphate buffer solution, with the best stability in pH 4.0-6.0 environment, easy peptide bond hydrolysis under alkaline conditions, and accelerated degradation at high temperatures; The molecule contains tryptophan and tyrosine, with a characteristic UV absorption peak at 280nm, which can be used for quantitative detection.

ACTH (1-39) is mainly synthesized and secreted by adrenocorticotropic hormone cells in the anterior pituitary gland, with a small amount locally synthesized by tissues such as the hypothalamus, placenta, and immune cells, and participates in paracrine regulation.
Precursor synthesis: POMC is generated by protease cleavage, and POMC can be cleaved into active peptides such as alpha melanocyte stimulating hormone (α - MSH), beta lipophilin (β - LPH), and beta endorphins, forming the "POMC derived peptide family" with interrelated functions.

Release mode: Pulse like release, with a pulse every 1-2 hours, superimposed with a circadian rhythm - secretion gradually decreases after falling asleep, reaching its lowest point from 0:00 to 2:00 at midnight, rapidly rising to its peak from 4:00 to 8:00 in the morning, maintaining a low level during the day, and then decreasing again after falling asleep, completely synchronized with the glucocorticoid rhythm.
Half life and metabolism: The half-life in circulation is only 7-12 minutes, while the half-life of intravenous injection of artificially synthesized ACTH (1-39) is 10-25 minutes. It is mainly oxidized and enzymatically inactivated by the liver, with a small amount excreted by the kidneys. It can bind to various proteins in the blood to delay metabolism.

ACTH (1-39) secretion is precisely regulated by the hypothalamic pituitary adrenal axis (HPA axis), forming an "activation feedback" loop to maintain a balance between basal secretion and stress response.
Upstream activation factor:
Corticotropin releasing hormone (CRH): secreted by the paraventricular nucleus of the hypothalamus, a core activating factor that binds to the CRH receptor of pituitary adrenocorticotropic hormone cells to promote ACTH synthesis and release.

The core physiological function of ACTH (1-39) is to specifically bind to MC2R (G protein coupled receptor) on the cell membrane of the adrenal cortex zona fasciculata and zona reticulata, initiate downstream signaling pathways, and drive steroid hormone synthesis.
Receptor activation: ACTH (1-39) N-terminal 1-24 binds to the extracellular domain of MC2R, inducing conformational changes in the receptor and activating the intracellular Gs protein.

Activation of cAMP PKA pathway: Gs protein activates adenylate cyclase (AC), catalyzing ATP to generate cAMP, increasing intracellular cAMP concentration, and activating protein kinase A (PKA).
Downstream effect activation: PKA phosphorylation activates three key targets:
Steroid synthesis acute regulatory protein (StAR): promotes the transport of cholesterol from the outer membrane to the inner membrane of mitochondria, with a rate limiting step;

Steroid synthases (CYP11A1, CYP17A1, CYP21A2) catalyze the conversion of cholesterol to pregnenolone, which in turn produces glucocorticoids and androgens;
Phosphorylase: promotes glycogen breakdown, generates ATP and NADPH, and provides energy and reducing power for hormone synthesis.

ACTH (1-39) is the primary regulatory factor for the synthesis and secretion of glucocorticoids, maintaining basal cortisol secretion under basal conditions and driving massive cortisol release during stress, maintaining metabolic homeostasis and stress adaptation.
Basic secretion maintenance: The physiological concentration of ACTH continuously stimulates the adrenal cortex, maintaining the basal level of cortisol (8am: 138-690nmol/L), ensuring normal metabolism of sugar, fat, and protein.

Stress induced surge: ACTH secretion can increase 10-20 times during stress, driving cortisol secretion to increase 5-10 times, with a peak of over 1700 nmol/L, meeting the energy supply and inflammation inhibition needs during stress.
Adrenal cortex nutritional function: Long term stimulation of ACTH promotes the proliferation and hypertrophy of the adrenal cortex fasciculus and reticular zone, maintaining the structural integrity and functional activity of the adrenal cortex; When ACTH is deficient, the adrenal cortex atrophy and hormone synthesis ability decrease.

ACTH (1-39) is the primary initiating factor of the body's stress response. Signals from physical stress (trauma, infection, pain), psychological stress (anxiety, fear, stress), metabolic stress (hypoglycemia, hunger), etc. are transmitted through the central nervous system to the hypothalamus, activating the CRH-ACTH cortisol axis, initiating the systemic anti stress response, and enhancing the body's adaptability and survival ability.

Rapid response (several minutes): Stress signals trigger the release of hypothalamic CRH, rapidly stimulating the secretion of pituitary ACTH. ACTH reaches the adrenal gland through the bloodstream, driving rapid release of cortisol, reaching its peak in 15-30 minutes, initiating multi system stress adaptation such as metabolism, inflammation, and immunity.

Continuous response (several hours to several days): During chronic stress, ACTH is continuously released in a pulsed manner, maintaining a high secretion state of cortisol, prolonging stress adaptation time, and avoiding stress damage; Simultaneously promoting adrenal cortex hyperplasia and enhancing long-term stress tolerance.
Stress termination and recovery: After stress is eliminated, cortisol inhibits the secretion of CRH and ACTH through negative feedback, causing a rapid decrease in ACTH levels. Cortisol returns to baseline levels, terminating the stress response and avoiding metabolic disorders, immune suppression, and other side effects caused by long-term high cortisol.

ACTH (1-39) promotes energy mobilization and supply through cortisol mediated metabolic reprogramming, ensuring the energy needs of important organs such as the brain and heart during stress.
Adaptation to glucose metabolism stress: Cortisol promotes hepatic gluconeogenesis (conversion of amino acids, lactate, and glycerol into glucose), inhibits peripheral tissue (muscle, fat) glucose uptake, increases blood sugar, and prioritizes the supply of brain and red blood cells; Simultaneously promoting glycogen breakdown, rapidly releasing glucose, and responding to acute hypoglycemic stress.

Fat metabolism stress adaptation: Cortisol activates lipase, promotes fat breakdown, releases glycerol and free fatty acids, glycerol is used for gluconeogenesis, and fatty acids serve as energy sources for organs such as muscles and the heart; Simultaneously inhibiting fat synthesis, reducing fat accumulation, and mobilizing the body's energy reserves.
Protein metabolism stress adaptation: Cortisol promotes muscle protein breakdown, releasing amino acids for hepatic gluconeogenesis and acute phase protein synthesis; Inhibit muscle protein synthesis, reduce non essential tissue energy consumption, and ensure efficient energy utilization during stress.

ACTH( 1-39) Peptide inhibits excessive inflammatory response and immune activation during stress through a dual pathway of cortisol mediated and direct action, avoiding inflammatory damage and autoimmune attack, and maintaining immune homeostasis.
Indirect anti-inflammatory (cortisol mediated): Cortisol inhibits inflammatory signaling pathways such as NF - κ B and MAPK, reducing the release of pro-inflammatory factors such as TNF - α, IL-6, and IL-1 β; Inhibit the infiltration and activation of inflammatory cells (neutrophils, macrophages);

Reduce the synthesis of inflammatory mediators such as prostaglandins and leukotrienes, and alleviate inflammatory damage.
Direct immune suppression (independent of cortisol): ACTH (1-39) directly binds to the surface MC2R/MC4R of immune cells (macrophages, T cells, B cells), inhibits the NF - κ B pathway, and reduces the secretion of pro-inflammatory cytokines; Promote immune cell apoptosis and reduce inflammatory cell infiltration; Inhibit T cell proliferation and differentiation, reduce autoantibody production, and avoid autoimmune damage.