Two versatile cofactors, flavin adenine dinucleotide and non-heme iron, involved in DNA repair and natural product halogenation

Cofactors assist enzymes with a variety of complex chemistries. Two versatile cofactors, flavin adenine dinucleotide (FAD) and non-heme iron, together with molecular oxygen as an oxidizing agent, perform a wide array of reactions. Hydroxylation in DNA repair is one example. AidB is an adaptive response protein that is up-regulated in the presence of alkylating agents. AidB contains FAD; however, the precise role of the FAD has been determined. AlkB, another adaptive response protein that is up-regulated in the presence of alkylating agents, is a member of the alpha-ketoglutarate (aKG) non-heme iron-dependent superfamily. It uses the cofactor non-heme iron, and the co-substrates molecular oxygen a: G, to remove alkylated adducts on DNA bases via hydroxylation. Two well characterized 1 homologues of AlkB, hABH2 and hABH3, also belong to the XKG/Fe(II)-dependent superfamily, but their substrate preference differ from that of AlkB. Furthermore, FAD and non-heme iron, again with molecular oxygen as an oxidizing agent, can perform halogenation chemistry. Flavin-dependent halogenasess perform halogenation reactions on aromatic substrates, while non-heme iron-dependent halogenases perform halogenations reactions on unactivated aliphatic substrates. I is a flavin-dependent halogenase that catalyzes the chlorination of free tryptophan to form 7-chlorotryptophan in the biosynthesis of rebeccamycin. CytC3 is an cxKG and non-heme iron-dependent halogenase that catalyzes the chlorination of L-2-aminobutyric acid bound to thiolation domain in the biosynthesis of yy-dichloroaminobutyrate.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2009

Author dc:creator

• Wong, Cintyu

Advisor dc:contributor.advisor

• Catherine L. Drennan.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/49749

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/49749