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Crystal structure of glucokinase from Balamuthia mandrillaris in complex with glucose
Structural highlights
Publication Abstract from PubMedInfection with pathogenic free-living amoebae, including Naegleria fowleri, Acanthamoeba spp., and Balamuthia mandrillaris, can lead to life-threatening illnesses, primarily because of catastrophic central nervous system involvement. Efficacious treatment options for these infections are lacking, and the mortality rate due to infection is high. Previously, we evaluated the N. fowleri glucokinase (NfGlck) as a potential target for therapeutic intervention, as glucose metabolism is critical for in vitro viability. Here, we extended these studies to the glucokinases from two other pathogenic free-living amoebae, including Acanthamoeba castellanii (AcGlck) and B. mandrillaris (BmGlck). While these enzymes are similar (49.3% identical at the amino acid level), they have distinct kinetic properties that distinguish them from each other. For ATP, AcGlck and BmGlck have apparent Km values of 472.5 and 41.0 muM, while Homo sapiens Glck (HsGlck) has a value of 310 muM. Both parasite enzymes also have a higher apparent affinity for glucose than the human counterpart, with apparent Km values of 45.9 muM (AcGlck) and 124 muM (BmGlck) compared to ~8 mM for HsGlck. Additionally, AcGlck and BmGlck differ from each other and other Glcks in their sensitivity to small molecule inhibitors, suggesting that inhibitors with pan-amoebic activity could be challenging to generate. Characterization of Glucokinases from Pathogenic Free-Living Amoebae.,Milanes JE, Suryadi J, Monaghan NP, Harding EM, Morris CS, Rozema SD, Khalifa MM, Golden JE, Phan IQ, Zigweid R, Abendroth J, Rice CA, McCord HT, Wilson S, Fenwick MK, Morris JC Antimicrob Agents Chemother. 2022 May 23:e0237321. doi: 10.1128/aac.02373-21. PMID:35604214[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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