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Target Concepts:
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Query: UMLS:C0038187 (
starvation
)
24,951
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Proteins responsible for P
i
homeostasis are critical for all life. In
Saccharomyces cerevisiae
, extracellular [P
i
] is "sensed" by the
inositol-hexakisphosphate kinase
(IP6K) that synthesizes the intracellular inositol pyrophosphate 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP
7
) as follows: during a period of P
i
starvation
, there is a decline in cellular [ATP]; the unusually low affinity of IP6Ks for ATP compels 5-InsP
7
levels to fall in parallel (Azevedo, C., and Saiardi, A. (2017)
Trends. Biochem. Sci.
42, 219-231. Hitherto, such P
i
sensing has not been documented in metazoans. Here, using a human intestinal epithelial cell line (HCT116), we show that levels of both 5-InsP
7
and ATP decrease upon [P
i
]
starvation
and subsequently recover during P
i
replenishment. However, a separate inositol pyrophosphate, 1,5-bisdiphosphoinositol 2,3,4,6-tetrakisphosphate (InsP
8
), reacts more dramatically (
i.e.
with a wider dynamic range and greater sensitivity). To understand this novel InsP
8
response, we characterized kinetic properties of the bifunctional 5-InsP
7
kinase/InsP
8
phosphatase activities of full-length diphosphoinositol pentakisphosphate kinases (PPIP5Ks). These data fulfil previously published criteria for any bifunctional kinase/phosphatase to exhibit concentration robustness, permitting levels of the kinase product (InsP
8
in this case) to fluctuate independently of varying precursor (
i.e.
5-InsP
7
) pool size. Moreover, we report that InsP
8
phosphatase activities of PPIP5Ks are strongly inhibited by P
i
(40-90% within the 0-1 mm range). For PPIP5K2, P
i
sensing by InsP
8
is amplified by a 2-fold activation of 5-InsP
7
kinase activity by P
i
within the 0-5 mm range. Overall, our data reveal mechanisms that can contribute to specificity in inositol pyrophosphate signaling, regulating InsP
8
turnover independently of 5-InsP
7
, in response to fluctuations in extracellular supply of a key nutrient.
...
PMID:The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis. 2812 3
