| Structural highlights
Function
GUAA_PLAF7 Catalyzes the conversion of xanthine monophosphate (XMP) to GMP in the presence of glutamine and ATP through an adenyl-XMP intermediate, which is the final step of de novo synthesis of GMP (PubMed:17868038, PubMed:21413787, PubMed:26592566, PubMed:32358899). The conversion of XMP to GMP involves the coordinated action of the glutamine amidotransferase (GATase) domain that catalyzes the hydrolysis of the amide side chain of glutamine producing ammonia and the ATP pyrophosphatase (ATPPase) domain that catalyzes the synthesis of adenyl-XMP intermediate from ATP (PubMed:17868038, PubMed:21413787, PubMed:26592566, PubMed:32358899). The ammonia produced by the GATase domain is tunnelled to the ATP-PPase domain where it attacks the adenyl-XMP intermediate generating GMP (PubMed:17868038, PubMed:21413787, PubMed:26592566, PubMed:32358899).[1] [2] [3] [4]
Publication Abstract from PubMed
GMP synthetase (GMPS), a key enzyme in the purine biosynthetic pathway performs catalysis through a coordinated process across two catalytic pockets for which the mechanism remains unclear. Crystal structures of Plasmodium falciparum GMPS in conjunction with mutational and enzyme kinetic studies reported here provide evidence that an 85 degrees rotation of the GATase domain is required for ammonia channelling and thus for the catalytic activity of this two-domain enzyme. We suggest that conformational changes in helix 371-375 holding catalytic residues and in loop 376-401 along the rotation trajectory trigger the different steps of catalysis, and establish the central role of Glu374 in allostery and inter-domain crosstalk. These studies reveal the mechanism of domain rotation and inter-domain communication, providing a molecular framework for the function of all single polypeptide GMPSs and form a solid basis for rational drug design targeting this therapeutically important enzyme.
Active site coupling in Plasmodium falciparum GMP synthetase is triggered by domain rotation.,Ballut L, Violot S, Shivakumaraswamy S, Thota LP, Sathya M, Kunala J, Dijkstra BW, Terreux R, Haser R, Balaram H, Aghajari N Nat Commun. 2015 Nov 23;6:8930. doi: 10.1038/ncomms9930. PMID:26592566[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bhat JY, Shastri BG, Balaram H. Kinetic and biochemical characterization of Plasmodium falciparum GMP synthetase. Biochem J. 2008 Jan 1;409(1):263-73. PMID:17868038 doi:10.1042/BJ20070996
- ↑ Bhat JY, Venkatachala R, Singh K, Gupta K, Sarma SP, Balaram H. Ammonia channeling in Plasmodium falciparum GMP synthetase: investigation by NMR spectroscopy and biochemical assays. Biochemistry. 2011 Apr 26;50(16):3346-56. PMID:21413787 doi:10.1021/bi1017057
- ↑ Ballut L, Violot S, Shivakumaraswamy S, Thota LP, Sathya M, Kunala J, Dijkstra BW, Terreux R, Haser R, Balaram H, Aghajari N. Active site coupling in Plasmodium falciparum GMP synthetase is triggered by domain rotation. Nat Commun. 2015 Nov 23;6:8930. doi: 10.1038/ncomms9930. PMID:26592566 doi:http://dx.doi.org/10.1038/ncomms9930
- ↑ Shivakumaraswamy S, Pandey N, Ballut L, Violot S, Aghajari N, Balaram H. Helices on Interdomain Interface Couple Catalysis in the ATPPase Domain with Allostery in Plasmodium falciparum GMP Synthetase. Chembiochem. 2020 Oct 1;21(19):2805-2817. PMID:32358899 doi:10.1002/cbic.202000158
- ↑ Ballut L, Violot S, Shivakumaraswamy S, Thota LP, Sathya M, Kunala J, Dijkstra BW, Terreux R, Haser R, Balaram H, Aghajari N. Active site coupling in Plasmodium falciparum GMP synthetase is triggered by domain rotation. Nat Commun. 2015 Nov 23;6:8930. doi: 10.1038/ncomms9930. PMID:26592566 doi:http://dx.doi.org/10.1038/ncomms9930
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