Crystal Structure and Enzymology of Solanum tuberosum Inositol Tris/Tetrakisphosphate Kinase 1 (StITPK1).

Inositol phosphates and their pyrophosphorylated derivatives are responsive to the phosphate supply and are agents of phosphate homeostasis and other aspects of physiology. It seems likely that the enzymes that interconvert these signals work against the prevailing milieu of mixed populations of competing substrates and products. The synthesis of inositol pyrophosphates is mediated in plants by two classes of ATP-grasp fold kinase: PPIP5 kinases, known as VIH, and members of the inositol tris/tetrakisphosphate kinase (ITPK) family, specifically ITPK1/2. A molecular explanation of the contribution of ITPK1/2 to inositol pyrophosphate synthesis and turnover in plants is incomplete: the absence of nucleotide in published crystal structures limits the explanation of phosphotransfer reactions, and little is known of the affinity of potential substrates and competitors for ITPK1. Herein, we describe a complex of ADP and StITPK1 at 2.26 Å resolution and use a simple fluorescence polarization approach to compare the affinity of binding of diverse inositol phosphates, inositol pyrophosphates, and analogues. By simple HPLC, we reveal the novel catalytic capability of ITPK1 for different inositol pyrophosphates and show Ins(3,4,5,6)P4 to be a potent inhibitor of the inositol pyrophosphate-synthesizing activity of ITPK1. We further describe the exquisite specificity of ITPK1 for the myo-isomer among naturally occurring inositol hexakisphosphates.

The impact of financial toxicity in gastrointestinal cancer patients.

BACKGROUND: Biopsychosocial distress screening is a critical component of comprehensive cancer care. Financial issues are a common source of distress in this patient population. This study uses a biopsychosocial distress screening tool to determine the factors associated with financial toxicity and the impact of these stressors on gastrointestinal cancer patients. METHODS: A 48-question, proprietary distress screening tool was administered to patients with gastrointestinal malignancies from 2009 to 2015. This validated, electronically-administered tool is given to all new patients. Responses were recorded on a 5-point Likert scale from 1 (not a problem) to 5 (very severe problem), with responses rated at ≥3 indicative of distress. Univariate and multivariate logistic regressions were used to analyze the data. RESULTS: Most of the 1,027 patients had colorectal (50%) or hepatobiliary (31%) malignancies. Additionally, 34% of all patients expressed a high level of financial toxicity. Age greater than 65 (odds ratio: 0.63, 95% confidence interval: 0.47-0.86, P < .01), college education (odds ratio: 0.53, 95% confidence interval: 0.38-0.73, P < .0001), being partnered (odds ratio: 0.61, 95% confidence interval: 0.44-0.84, P < .01), and annual income greater than $40,000 (odds ratio: 0.27, 95% confidence interval: 0.19-0.38, P < .0001) were all protective against financial toxicity on univariate analysis. Also, heavy tobacco use was associated significantly with increased distress on univariate analysis (odds ratio: 2.79, 95% confidence interval: 1.38-5.78, P < .01). With the exception of partnered status (odds ratio: 1.18, 95% confidence interval: 0.76-1.85, P = .46), all these variables retained their significant association with financial toxicity in the multivariate model. CONCLUSION: Financial toxicity impacts a large number of cancer patients. Further study of at-risk populations may identify patients who would benefit from pre-emptive education and counseling interventions as part of their routine cancer care.