Effects of heme ligand mutations including a pathogenic variant, H65R, on the properties of human cystathionine beta-synthase

Biochemistry
Sunil OjhaRuma Banerjee

Abstract

Human cystathionine beta-synthase is a hemeprotein that catalyzes a pyridoxal phosphate (PLP)-dependent condensation of serine and homocysteine into cystathionine. Biophysical characterization of this enzyme has led to the assignment of the heme ligands as histidine and cysteinate, respectively, which has recently been confirmed by crystal structure determination of the catalytic core of the protein. Using site-directed mutagenesis, we confirm that C52 and H65 represent the thiolate and histidine ligands to the heme. Conversion of C52 to alanine or serine results in spectral properties of the resulting hemeprotein that are consistent with the loss of a thiolate ligand. Thus, the Soret peak blue-shifts from 428 to 415 and 417 nm in the ferric forms of the C52S and C52A mutants, respectively, and from 450 to 423 nm in the ferrous states of both mutants. Addition of CO to the dithionite-reduced ferrous C52 mutants results in spectra with Soret peaks at 420 nm. EPR spectroscopy of the ferric C52 variants reveals the predominance of a high-spin species. The H65R mutant, a variant described in a homocystinuric patient, has Soret peaks at 424, 421, and 420 nm in the ferric, ferrous, and ferrous CO states, respectively. EPR spectroscop...Continue Reading

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Citations

May 22, 2010·Journal of Inherited Metabolic Disease·Jana KopeckáViktor Kožich
Apr 11, 2003·Biochimica Et Biophysica Acta·Ruma BanerjeeShin Taoka
Apr 11, 2003·Biochimica Et Biophysica Acta·Markus MeierPeter Burkhard
May 31, 2007·Natural Product Reports·Sangita SinghRuma Banerjee
Sep 8, 2009·Archives of Biochemistry and Biophysics·Laura CelanoBeatriz Alvarez
Dec 8, 2004·Archives of Biochemistry and Biophysics·Ruma Banerjee, Cheng-Gang Zou
Jun 21, 2005·Biochimica Et Biophysica Acta·Anna PrudovaRuma Banerjee
Oct 22, 2014·Journal of Inherited Metabolic Disease·Petra MelenovskáViktor Kožich
Sep 6, 2002·The Journal of Biological Chemistry·Ko Eto, Hideo Kimura
Oct 21, 2016·The Journal of Biological Chemistry·Michael T RingelThomas Brüser
Jun 3, 2004·The Journal of Nutrition·Naomi K Fukagawa, Richard A Galbraith
Apr 12, 2002·The Journal of Biological Chemistry·Shinichi Taoka, Ruma Banerjee
Feb 19, 2008·Biochemistry·Sebastián CarballalBeatriz Alvarez
Nov 8, 2017·Chemical Reviews·Milos R FilipovicRuma Banerjee
Feb 2, 2021·ACS Omega·Dayana BenchoamBeatriz Alvarez

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