Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0847097 (
acidity
)
15,165
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Renal gastrinoma has not been previously reported. A 12-year-old boy with Zollinger-Ellison syndrome was found to have a renal tumor. No other tumor was detectable by imaging techniques, and selective venous sampling for gastrin showed a significant renal vein to vena cava gradient. Nephrectomy was performed, and examination of the tumor showed typical histologic features of an endocrine tumor. G cells were apparent by electron microscopy, and immunoperoxidase staining for gastrin,
neuron-specific enolase
, and chromogranin were positive. The gastrin content was unusually low for gastrinomas: 128 pg/g. Following nephrectomy, fasting gastrin and secretin stimulation testing were normal. Basal
acidity
was reduced by 60% but remained elevated at 39 mmol H +/h (hydrogen ion per hour). We speculate that renal gastrinoma may be characterized by uniquely poor gastrin storage and that curative resection of all gastrinoma tissue may not necessarily be associated with immediate complete suppression of hyperacidity.
...
PMID:Zollinger-Ellison syndrome associated with a renal gastrinoma in a child. 287 87
We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with a previously unknown mode of action, is a potent inhibitor of the glycolytic enzyme, Enolase. SF2312 can only be synthesized as a racemic-diastereomeric mixture. However, co-crystal structures with
Enolase 2
(
ENO2
) have consistently shown that only the (3
S
,5
S
)-enantiomer binds to the active site. The
acidity
of the alpha proton at C-3, which deprotonates under mildly alkaline conditions, results in racemization; thus while the separation of four enantiomeric intermediates was achieved via chiral High Performance Liquid Chromatography (HPLC) of the fully protected intermediate, deprotection inevitably nullified enantiopurity. To prevent epimerization of the C-3, we designed and synthesized MethylSF2312, ((1,5-dihydroxy-3-methyl-2-oxopyrrolidin-3-yl)phosphonic acid), which contains a fully-substituted C-3 alpha carbon. As a racemic-diastereomeric mixture, MethylSF2312 is equipotent to SF2312 in enzymatic and cellular systems against Enolase. Chiral HPLC separation of a protected MethylSF2312 precursor resulted in the efficient separation of the four enantiomers. After deprotection and inevitable re-equilibration of the anomeric C-5, (3
S
)-MethylSF2312 was up to 2000-fold more potent than (3
R
)-MethylSF2312 in an isolated enzymatic assay. This observation strongly correlates with biological activity in both human cancer cells and bacteria for the 3
S
enantiomer of SF2312. Novel X-ray structures of human
ENO2
with chiral and racemic MethylSF2312 show that only (3
S,
5
S)
-enantiomer occupies the active site. Enolase inhibition is thus a direct result of binding by the (3
S,
5
S)
-enantiomer of MethylSF2312. Concurrent with these results for MethylSF2312, we contend that the (3
S
,5
S
)-SF2312 is the single active enantiomer of inhibitor SF2312.
...
PMID:The 3
S
Enantiomer Drives Enolase Inhibitory Activity in SF2312 and Its Analogues. 3132 42
