6DA0

Crystal structure of glucokinase (NfHK) from Naegleria fowleri

Summary for 6DA0

• Entry DOI: 10.2210/pdb6da0/pdb
• Descriptor: Glucokinase, beta-D-glucopyranose, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (4 entities in total)
• Functional Keywords: ssgcid, structural genomics, naegleria fowleri, glucokinase, nfhk, seattle structural genomics center for infectious disease, transferase
• Biological source: Naegleria fowleri
• Total number of polymer chains: 1
• Total formula weight: 51132.24

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2018-05-01, release date: 2018-05-09, Last modification date: 2023-10-04)

Primary citation

Milanes, J.E.,Suryadi, J.,Abendroth, J.,Van Voorhis, W.C.,Barrett, K.F.,Dranow, D.M.,Phan, I.Q.,Patrick, S.L.,Rozema, S.D.,Khalifa, M.M.,Golden, J.E.,Morris, J.C.
Enzymatic and Structural Characterization of theNaegleria fowleriGlucokinase.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: Infection with the free-living amoeba leads to life-threatening primary amoebic meningoencephalitis. Efficacious treatment options for these infections are limited, and the mortality rate is very high (∼98%). Parasite metabolism may provide suitable targets for therapeutic design. Like most other organisms, glucose metabolism is critical for parasite viability, being required for growth in culture. The first enzyme required for glucose metabolism is typically a hexokinase (HK), which transfers a phosphate from ATP to glucose. The products of this enzyme are required for both glycolysis and the pentose phosphate pathway. However, the genome lacks an obvious HK homolog and instead harbors a glucokinase (Glck). The Glck (NfGlck) shares limited (25%) amino acid identity with the mammalian host enzyme ( Glck), suggesting that parasite-specific inhibitors with anti-amoeba activity can be generated. Following heterologous expression, NfGlck was found to have a limited hexose substrate range, with the greatest activity observed with glucose. The enzyme had apparent values of 42.5 ± 7.3 μM and 141.6 ± 9.9 μM for glucose and ATP, respectively. The NfGlck structure was determined and refined to 2.2-Å resolution, revealing that the enzyme shares greatest structural similarity with the Glck. These similarities include binding modes and binding environments for substrates. To identify inhibitors of NfGlck, we screened a small collection of inhibitors of glucose-phosphorylating enzymes and identified several small molecules with 50% inhibitory concentration values of <1 μM that may prove useful as hit chemotypes for further leads and therapeutic development against .

PubMed: 30783001
DOI: 10.1128/AAC.02410-18

Experimental method

X-RAY DIFFRACTION (2.2 Å)