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The Structure of Carbonic Anhydrase IX Is Adapted for Low-pH Catalysis
- Source :
- Biochemistry. 55(33)
- Publication Year :
- 2016
-
Abstract
- Human carbonic anhydrase IX (hCA IX) expression in many cancers is associated with hypoxic tumors and poor patient outcome. Inhibitors of hCA IX have been used as anticancer agents with some entering Phase I clinical trials. hCA IX is transmembrane protein whose catalytic domain faces the extracellular tumor milieu, which is typically associated with an acidic microenvironment. Here, we show that the catalytic domain of hCA IX (hCA IX-c) exhibits the necessary biochemical and biophysical properties that allow for low pH stability and activity. Furthermore, the unfolding process of hCA IX-c appears to be reversible, and its catalytic efficiency is thought to be correlated directly with its stability between pH 3.0 and 8.0 but not above pH 8.0. To rationalize this, we determined the X-ray crystal structure of hCA IX-c to 1.6 Å resolution. Insights from this study suggest an understanding of hCA IX-c stability and activity in low-pH tumor microenvironments and may be applicable to determining pH-related effects on enzymes.
- Subjects :
- 0301 basic medicine
Tumor microenvironment
Circular dichroism
Chemistry
Circular Dichroism
Carbonic Anhydrase IX
Hydrogen-Ion Concentration
Lyase
Crystallography, X-Ray
Biochemistry
Transmembrane protein
Catalysis
Mass Spectrometry
Recombinant Proteins
Article
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
030220 oncology & carcinogenesis
Enzyme Stability
Extracellular
Catalytic efficiency
Subjects
Details
- ISSN :
- 15204995
- Volume :
- 55
- Issue :
- 33
- Database :
- OpenAIRE
- Journal :
- Biochemistry
- Accession number :
- edsair.doi.dedup.....8c5705a8e6f374b4798fe6f11a2b239b