Chemical Identity

Property	Value
Name	α-Melanocyte-Stimulating Hormone
Gene	POMC (chromosome 2p23.3)
Sequence	Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂
Length	13 amino acids
N-terminal	Acetylated (serine)
C-terminal	Amidated (valine)
MW	1664.9 Da
PDB Structures	2BTK (NMR)

POMC Processing

POMC (241 aa)
    → ACTH (1-39) + α-MSH (1-13) + CLIP (18-39)
    → β-LPH → γ-MSH (1-11) + β-endorphin (1-31)
    → β-MSH (1-18) + β-LPH (42-91)

Tissue-Specific Processing

Tissue	Products	Enzymes
Anterior pituitary	ACTH, β-LPH	PC1/3
Intermediate lobe	α-MSH, CLIP, β-endorphin	PC2, carboxypeptidase E
Hypothalamus	α-MSH, ACTH	PC2

Receptors (Melanocortin System)

Receptor	Gene	Distribution	Primary Effects
MC1R	MC1R	Skin (melanocytes)	Pigmentation
MC2R	MC2R	Adrenal cortex	ACTH receptor (cortisol)
MC3R	MC3R	Brain, gut	Energy homeostasis
MC4R	MC4R	Brain (hypothalamus)	Appetite, body weight
MC5R	MC5R	Exocrine glands	Sebaceous secretion

Melanocortin Pathway

POMC neuron → α-MSH → MC4R (hypothalamus) → ↓ Appetite
     ↑                        ↓
Leptin              AgRP (antagonist) → ↑ Appetite

Physiological Functions

Pigmentation

• α-MSH → MC1R on melanocytes → ↑ Melanin synthesis
• Red hair (MC1R variants) → reduced α-MSH sensitivity → pheomelanin
• Tanning response: UV → POMC → α-MSH → pigmentation

Appetite Regulation

• α-MSH is the key satiety signal from POMC neurons
• MC4R activation suppresses food intake

Learn more: Therapeutic Peptides on Wikipept

• AgRP (antagonist) blocks MC4R → stimulates feeding
• Leptin stimulates POMC neurons → ↑ α-MSH

Anti-inflammatory

• α-MSH is a potent anti-inflammatory peptide
• Inhibits NF-κB, reduces TNF-α, IL-1β, IL-6
• Used in experimental anti-inflammatory therapy

Clinical Significance

Setmelanotide (Imcivree®)

• MC4R agonist (approved 2020)
• Indications: POMC deficiency, PCSK1 deficiency, Bardet-Biedl syndrome (MC4R mutation)
• Mechanism: Activates MC4R to reduce appetite
• Weight loss: 10-15% body weight in responders

Melanocortin System in Obesity

• MC4R mutations are the most common monogenic cause of obesity
• MC3R variants associated with obesity susceptibility
• AgRP antagonists under investigation

Other Clinical Applications

• Vitiligo: α-MSH analogs for repigmentation
• Inflammatory bowel disease: Anti-inflammatory effects
• Sexual dysfunction: Melanotan II (MC4R agonist, investigational)

Manufacturing

• SPPS (Fmoc): Standard solid-phase synthesis
• N-terminal acetylation: Required for full activity
• Purification: RP-HPLC
• Melanotan II: Modified α-MSH analog (cyclized)

References

1. Catania A, et al. “α-MSH in fever and systemic inflammation.” Annual Review of Pharmacology and Toxicology 38:365-390, 1998. doi:10.1146/annurev.ph.58.030196.000313
2. Cone RD. “Anatomy and regulation of the central melanocortin system.” Nature Neuroscience 8:571-578, 2005.
3. Kuo LE, et al. “Setmelanotide for obesity.” New England Journal of Medicine 383:2401-2410, 2020.
4. Catania A, et al. “α-MSH as a therapeutic anti-inflammatory peptide.” International Journal of Immunopathology and Pharmacology 19:1-8, 2006.
5. Mountjoy KG, et al. “The cloning of a family of genes that encode the melanocortin receptors.” Science 257:1248-1251, 1992.