Structural Basis for the Selective Binding of Inhibitors to 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Staphylococcus aureus and Escherichia coli. | LitMetric
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Published: June 2016
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Article Abstract
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a member of the folate biosynthesis pathway found in prokaryotes and lower eukaryotes that catalyzes the pyrophosphoryl transfer from the ATP cofactor to a 6-hydroxymethyl-7,8-dihydropterin substrate. We report the chemical synthesis of a series of S-functionalized 8-mercaptoguanine (8MG) analogues as substrate site inhibitors of HPPK and quantify binding against the E. coli and S. aureus enzymes (EcHPPK and SaHPPK). The results demonstrate that analogues incorporating acetophenone-based substituents have comparable affinities for both enzymes. Preferential binding of benzyl-substituted 8MG derivatives to SaHPPK was reconciled when a cryptic pocket unique to SaHPPK was revealed by X-ray crystallography. Differential chemical shift perturbation analysis confirmed this to be a common mode of binding for this series to SaHPPK. One compound (41) displayed binding affinities of 120 nM and 1.76 μM for SaHPPK and EcHPPK, respectively, and represents a lead for the development of more potent and selective inhibitors of SaHPPK.
Thiamine is metabolized into thiamine pyrophosphate (TPP), an essential enzyme cofactor. Previous work has shown that oxythiamine, a thiamine analog, is metabolized by thiamine pyrophosphokinase (TPK) into oxythiamine pyrophosphate within the malaria parasite and then inhibits TPP-dependent enzymes, killing the parasite and . To identify a more potent antiplasmodial thiamine analog, 11 commercially available compounds were tested against and .
Gene expression and proper downstream cellular functions upon facing environmental shifts depend on the combined and cooperative regulation of genetic networks. Here, we identified cAMP receptor protein (CRP) as a master regulator of (p)ppGpp (guanosine tetra- and penta-phosphate) homeostasis. Via CRP-mediated direct transcriptional regulation of the (p)ppGpp synthetase/hydrolase RelA and SpoT, cAMP-CRP stimulates pervasive accumulation of (p)ppGpp under glucose-limiting conditions.
Ample studies attribute cognitive decline in Alzheimer's disease to amyloid-β deposition . However, brain amyloid-β accumulation that saturates years before the manifestation of clinical symptoms is dissociated with cognitive decline of the disease . It is unknown how these two processes are mechanistically linked.
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthesis pathway. It catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). HPPK is essential for microorganisms but is absent in mammals.
Department of Neurology, Zhongshan Hospital; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science; Institutes of Brain Science; National Clinical Research Center for Aging and Medicine, Huashan Hospital; Fudan University.
Thiamine deficiency is linked to severe brain disorders like Wernicke encephalopathy and Korsakoff syndrome, but how this happens is not fully understood.
The study analyzed specific genes involved in thiamine metabolism in different tissues (brain, kidney, liver) of mice, finding that expression of thiamine pyrophosphokinase-1 (TPK) was significantly lower in the brain.
Results showed that low TPK levels in the brain increase vulnerability to thiamine deficiency, leading to neuron loss and other harmful effects, suggesting TPK plays a crucial role in brain health.
