Crystal Structures of Cystathionine β-Synthase from Saccharomyces cerevisiae: One Enzymatic Step at a Time

Yupeng Tu, Cheryl A. Kreinbring, Megan Hill, Cynthia Liu, Gregory A. Petsko, Christopher D. McCune, David B Berkowitz, Dali Liu, Dagmar Ringe

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Cystathionine β-synthase (CBS) is a key regulator of sulfur amino acid metabolism, taking homocysteine from the methionine cycle to the biosynthesis of cysteine via the trans-sulfuration pathway. CBS is also a predominant source of H2S biogenesis. Roles for CBS have been reported for neuronal death pursuant to cerebral ischemia, promoting ovarian tumor growth, and maintaining drug-resistant phenotype by controlling redox behavior and regulating mitochondrial bioenergetics. The trans-sulfuration pathway is well-conserved in eukaryotes, but the analogous enzymes have different enzymatic behavior in different organisms. CBSs from the higher organisms contain a heme in an N-terminal domain. Though the presence of the heme, whose functions in CBSs have yet to be elucidated, is biochemically interesting, it hampers UV-vis absorption spectroscopy investigations of pyridoxal 5′-phosphate (PLP) species. CBS from Saccharomyces cerevisiae (yCBS) naturally lacks the heme-containing N-terminal domain, which makes it an ideal model for spectroscopic studies of the enzymological reaction catalyzed and allows structural studies of the basic yCBS catalytic core (yCBS-cc). Here we present the crystal structure of yCBS-cc, solved to 1.5 Å. Crystal structures of yCBS-cc in complex with enzymatic reaction intermediates have been captured, providing a structural basis for residues involved in catalysis. Finally, the structure of the yCBS-cc cofactor complex generated by incubation with an inhibitor shows apparent off-pathway chemistry not normally seen with CBS.

Original languageEnglish (US)
Pages (from-to)3134-3145
Number of pages12
JournalBiochemistry
Volume57
Issue number22
DOIs
StatePublished - Jun 5 2018

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Cystathionine
Heme
Yeast
Saccharomyces cerevisiae
Catalytic Domain
Crystal structure
Sulfur Amino Acids
Reaction intermediates
Pyridoxal Phosphate
Biosynthesis
Homocysteine
Ultraviolet spectroscopy
Absorption spectroscopy
Metabolism
Methionine
Catalysis
Cysteine
Tumors
Brain Ischemia
Eukaryota

ASJC Scopus subject areas

  • Biochemistry

Cite this

Tu, Y., Kreinbring, C. A., Hill, M., Liu, C., Petsko, G. A., McCune, C. D., ... Ringe, D. (2018). Crystal Structures of Cystathionine β-Synthase from Saccharomyces cerevisiae: One Enzymatic Step at a Time. Biochemistry, 57(22), 3134-3145. https://doi.org/10.1021/acs.biochem.8b00092

Crystal Structures of Cystathionine β-Synthase from Saccharomyces cerevisiae : One Enzymatic Step at a Time. / Tu, Yupeng; Kreinbring, Cheryl A.; Hill, Megan; Liu, Cynthia; Petsko, Gregory A.; McCune, Christopher D.; Berkowitz, David B; Liu, Dali; Ringe, Dagmar.

In: Biochemistry, Vol. 57, No. 22, 05.06.2018, p. 3134-3145.

Research output: Contribution to journalArticle

Tu, Y, Kreinbring, CA, Hill, M, Liu, C, Petsko, GA, McCune, CD, Berkowitz, DB, Liu, D & Ringe, D 2018, 'Crystal Structures of Cystathionine β-Synthase from Saccharomyces cerevisiae: One Enzymatic Step at a Time', Biochemistry, vol. 57, no. 22, pp. 3134-3145. https://doi.org/10.1021/acs.biochem.8b00092
Tu, Yupeng ; Kreinbring, Cheryl A. ; Hill, Megan ; Liu, Cynthia ; Petsko, Gregory A. ; McCune, Christopher D. ; Berkowitz, David B ; Liu, Dali ; Ringe, Dagmar. / Crystal Structures of Cystathionine β-Synthase from Saccharomyces cerevisiae : One Enzymatic Step at a Time. In: Biochemistry. 2018 ; Vol. 57, No. 22. pp. 3134-3145.
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