Azaserine

Azaserine is a naturally occurring serine derivative diazo compound with antineoplastic and antibiotic properties deriving from its action as a purinergic antagonist and structural similarity to glutamine. Azaserine acts by competitively inhibiting glutamine amidotransferase, a key enzyme responsible for glutamine metabolism.

Azaserine

Clinical data
ATC code	none
Identifiers
IUPAC name O-(2-Diazoacetyl)-L-serine
CAS Number	115-02-6 Y
PubChem CID	5284344
ChemSpider	16735688 Y
UNII	87299V3Q9W
KEGG	D03032 Y
ChEBI	CHEBI:74846 N
ChEMBL	ChEMBL1095699 Y
CompTox Dashboard (EPA)	DTXSID9020118
ECHA InfoCard	100.003.692
Chemical and physical data
Formula	C5H7N3O4
Molar mass	173.128 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(OC[C@H](N)C(O)=O)/C=[N+]=[N-]
InChI InChI=1S/C5H7N3O4/c6-3(5(10)11)2-12-4(9)1-8-7/h1,3H,2,6H2,(H,10,11)/t3-/m0/s1 Y Key:MZZGOOYMKKIOOX-VKHMYHEASA-N Y
NY (what is this?)  (verify)

Mechanism of Action

Azaserine inhibits the rate limiting step of the metabolic hexosamine pathway and irreversibly inhibits γ-glutamyltransferase by acting directly at the substrate-binding pocket. Independent of hexosamine pathway inhibition, azaserine has been demonstrated to protect against hyperglycemic endothelial damage by elevating serum concentrations of manganese-superoxide dismutase, directly reducing the concentration of reactive oxygen species.

Azaserine also downregulates the expression of VCAM-1 and ICAM-1 in response to TNF-α, and research indicates that it may have potential in identifying the L-leucine-favoring system transporter in human T-lymphocytes.

Properties

Azaserine has a solubility of 50 mg/mL in water, a melting point of 146-162 °C, a vapor pressure of 1.53x10⁻¹⁰mmHg at 25 °C, and decomposes before melting.

References

• Segel GB, Woodlock TJ, Murant FG, Lichtman MA (October 1989). "Photoinhibition of 2-amino-2-carboxybicyclo[2,2,1]heptane transport by O-diazoacetyl-L-serine. An initial step in identifying the L-system amino acid transporter". The Journal of Biological Chemistry. 264 (28): 16399–402. doi:10.1016/S0021-9258(19)84720-8. PMID 2789219.
• Hull RL, Zraika S, Udayasankar J, Kisilevsky R, Szarek WA, Wight TN, Kahn SE (November 2007). "Inhibition of glycosaminoglycan synthesis and protein glycosylation with WAS-406 and azaserine result in reduced islet amyloid formation in vitro". American Journal of Physiology. Cell Physiology. 293 (5): C1586–93. doi:10.1152/ajpcell.00208.2007. PMC 2365901. PMID 17804609.
• Wada K, Hiratake J, Irie M, Okada T, Yamada C, Kumagai H, Suzuki H, Fukuyama K (July 2008). "Crystal structures of Escherichia coli gamma-glutamyltranspeptidase in complex with azaserine and acivicin: novel mechanistic implication for inhibition by glutamine antagonists". Journal of Molecular Biology. 380 (2): 361–72. doi:10.1016/j.jmb.2008.05.007. PMID 18555071.
• Rajapakse AG, Ming XF, Carvas JM, Yang Z (March 2009). "The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects" (PDF). American Journal of Physiology. Heart and Circulatory Physiology. 296 (3): H815–22. doi:10.1152/ajpheart.00756.2008. PMID 19136606.
• Lebedeva ZI, Kabanova EA, Berezov TT (March 1986). "6-diazo-5-oxo-L-norleucine and azaserine as affinity inhibitors of glutamin(asparagin)ase". Biochemistry International. 12 (3): 413–20. PMID 3707592.