Contrasting behaviors of mutant cystathionine beta-synthase enzymes associated with pyridoxine response

Human Mutation
X ChenW D Kruger

Abstract

Cystathionine beta-synthase (CBS) deficiency is a recessive genetic disorder characterized by extremely elevated levels in plasma homocysteine. Patients homozygous for the I278T or R266K mutations respond clinically to pharmacologic doses of pyridoxine, the precursor of a cofactor for the enzyme, 5'-pyridoxal phosphate (PLP). Here we test the hypothesis that these mutations are pyridoxine responsive because they lower the affinity of the enzyme for PLP. We show that recombinant R266K has 30 to 100% of the specific activity of the wild-type enzyme, while I278T only has only 1 to 5% activity. Kinetic studies show that the decreased activity in both enzymes is due to reduced turnover rate and not substrate binding. Neither I278T nor R266K appear to greatly affect multimer status of the enzyme. The R266K enzyme has reduced affinity for PLP compared to the wild-type enzyme, providing a mechanism for the pyridoxine response observed in patients. Surprisingly, the I278T enzyme does not have altered affinity for PLP. To confirm that this was not an in vitro artifact, we examined pyridoxine response in mice that stably express human I278T as their sole source of CBS activity. These mice have extremely elevated plasma homocysteine levels...Continue Reading

References

Jul 1, 1973·Pediatric Research·B W UhlendorfS H Mudd
Jul 5, 1994·Proceedings of the National Academy of Sciences of the United States of America·W D Kruger, D R Cox
May 20, 1998·Nature Genetics·X Shan, W D Kruger
Sep 17, 1998·The Journal of Biological Chemistry·S TaokaR Banerjee
May 25, 1999·Human Mutation·J P KrausM Gaustadnes
May 19, 2001·American Journal of Human Genetics·M JanosíkV Kozich
May 14, 2005·Antioxidants & Redox Signaling·Kwang-Hwan Jhee, Warren D Kruger

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Citations

Aug 2, 2015·Journal of Inherited Metabolic Disease·Sapna GuptaWarren D Kruger
Feb 11, 2011·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·S Harvey Mudd
Aug 18, 2009·American Journal of Obstetrics and Gynecology·Carla A MartinezKit Sing Au
Jun 2, 2007·Molecular Genetics and Metabolism·Laishram R SinghWarren D Kruger
Oct 22, 2014·Journal of Inherited Metabolic Disease·Petra MelenovskáViktor Kožich
Dec 1, 2017·Antioxidants & Redox Signaling·María A Pajares, Dolores Pérez-Sala
May 31, 2007·Natural Product Reports·Sangita SinghRuma Banerjee
Jun 27, 2019·Journal of Inherited Metabolic Disease·Sapna GuptaWarren D Kruger
Feb 1, 2020·Genome Medicine·Song SunFrederick P Roth
May 6, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sapna GuptaWarren D Kruger

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