Human polycomb 2 protein is a SUMO E3 ligase and alleviates substrate-induced inhibition of cystathionine beta-synthase sumoylation.

Full Abstract

Human cystathionine beta-synthase (CBS) catalyzes the first irreversible step in the transsulfuration pathway and commits homocysteine to the synthesis of cysteine. Mutations in CBS are the most common cause of severe hereditary hyperhomocysteinemia. A yeast two-hybrid approach to screen for proteins that interact with CBS had previously identified several components of the sumoylation pathway and resulted in the demonstration that CBS is a substrate for sumoylation. In this study, we demonstrate that sumoylation of CBS is enhanced in the presence of human polycomb group protein 2 (hPc2), an interacting partner that was identified in the initial yeast two-hybrid screen. When the substrates for CBS, homocysteine and serine for cystathionine generation and homocysteine and cysteine for H(2)S generation, are added to the sumoylation mixture, they inhibit the sumoylation reaction, but only in the absence of hPc2. Similarly, the product of the CBS reaction, cystathionine, inhibits sumoylation in the absence of hPc2. Sumoylation in turn decreases CBS activity by approximately 28% in the absence of hPc2 and by 70% in its presence. Based on these results, we conclude that hPc2 serves as a SUMO E3 ligase for CBS, increasing the efficiency of sumoylation. We also demonstrate that gamma-cystathionase, the second enzyme in the transsulfuration pathway is a substrate for sumoylation under in vitro conditions. We speculate that the role of this modification may be for nuclear localization of the cysteine-generating pathway under conditions where nuclear glutathione demand is high.

Author information

Author/s: Agrawal, Nitish (N); Banerjee, Ruma (R);

Affiliation: Department of Biological Chemistry, School of Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: PloS one (PLoS One), published in United States. (Language: eng)

Reference: 2008-; vol 3 (issue 12) : pp e4032

Dates: Created 2008/12/24; Completed 2009/02/19; Revised 2009/06/16;

PMID: 19107218, status: MEDLINE (last retrieved date: 6/16/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Cystathionine beta-Synthase - antagonists & inhibitors; metabolism
Cysteine - pharmacology
Enzyme Activation - drug effects
Homocysteine - pharmacology
Humans
Models, Molecular

Protein Processing, Post-Translational - drug effects; physiology
Repressor Proteins - metabolism; physiology
S-Adenosylmethionine - pharmacology
SUMO-1 Protein - metabolism
Serine - pharmacology
Ubiquitin-Protein Ligases - metabolism; physiology

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Repressor Proteins (0) ; SUMO-1 Protein (0) ; polycomb group proteins (0) ; S-Adenosylmethionine (29908-03-0) ; Homocysteine (454-28-4) ; Cysteine (52-90-4) ; Serine (56-45-1) ; Cystathionine beta-Synthase (EC 4.2.1.22) ; Ubiquitin-Protein Ligases (EC 6.3.2.19)

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