Histone demethylases LSD1 JMJC Lysine demethylase A B S T R A C TReversible histone methylation has emerged in the last few years as an important mechanism of epigenetic regulation. Histone methyltransferases and demethylases have been identified as contributing factors in the development of several diseases, especially cancer. Therefore, they have been postulated to be new drug targets with high therapeutic potential. Here, we review histone demethylases with a special focus on their potential role in oncology drug discovery. We present an overview over the different classes of enzymes, their biochemistry, selected data on their role in physiology and already available inhibitors.ª 2012 Federation of European Biochemical Societies.Published by Elsevier B.V. All rights reserved. IntroductionHistone methylation had long been thought to be an irreversible process but since (Metzger et al., 2005Shi et al., 2004) it is known that histones, but also other proteins (Huang et al., 2007a;Nicholson and Chen, 2009), are also subject to active enzymatic demethylation (Agger et al., 2008). Reversible histone methylation has been shown to be involved in gene regulation and hence is interesting as a target for therapeutic intervention (Shi, 2007;Yoshimi and Kurokawa, 2011). Very rapidly inhibitors of these enzymes were identified and already show promise for drug development (Lohse et al., 2011a;Spannhoff et al., 2009a). Here, we present an overview over the different classes of histone demethylases, their biochemistry, selected evidence for their role in oncogenesis and inhibitor studies. Reversible histone methylationMethylation of histones occurs posttranslationally both on lysines as well as arginines (Trievel, 2004). Methyltransferases use the cofactor S-adenosyl methionine (SAM) to transfer a methyl group onto the basic side chains of these amino acids within proteins.

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Background: Allene oxide synthases (AOS) of the CYP74 family are present in plants, but AOS of fungi have not been characterized. Results: Expression of dioxygenase-cytochrome P450 fusion proteins of Aspergillus terreus reveals a novel AOS. Conclusion: AOS of A. terreus forms compound II with catalytic similarities to CYP74 and CYP8A1. Significance: The fungal AOS protein sequence is unique with little homology to CYP74.

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late systemic metabolic homeostasis, and it potentiates the effects of insulin ( 1, 2 ). Oleic acid modulates infl ammation, and both oleic acid and oleoylethanolamine suppress food intake ( 3-6 ). Mono-and polyunsaturated fatty acids can be oxygenated by P450, heme-dependent fatty acid dioxygenases, and lipoxygenases to a long list of biological mediators, eicosanoids, and oxylipins. Oxidation of arachidonic acid in humans and linoleic and ␣ -linolenic acids in plants has been studied extensively ( 7-10 ). In contrast to plants and animals, some microorganisms can also oxygenate monounsaturated fatty acids effi ciently to oxylipins of physiological interest ( 11,12 ).Enzymatic oxidation of octadecenoic acids to hydroperoxides has been reported in bacteria (e.g., Pseudomonas aeruginosa ) and fungi (e.g., Gaeumannomyces graminis , aspergilli). P. aeruginosa expresses a prominent enzyme in the periplasm that oxidizes oleic acid sequentially to (10 S )-hydroperoxy-(8 E )-octadecenoic acid (10 S -HpOME ) and (7 S ,10 S )-dihydroxy-(8 E )-octadecenoic acid ( 12 ). Oleic acid is oxidized by G. graminis and several aspergilli sequentially to (8 R )-hydroperoxyoleic acid (8 R -HpOME) and to diols, e.g., (7 S ,8 S )-dihydroxyoleic acid (7 S ,8 SDiHOME ) , 5 S ,8 R -DiHOME, and 8 R ,11 S -DiHOME ( 13-15 ). These oxylipins affect sexual and asexual sporulation in Aspergillus nidulans ( 14 ), and the key intermediate, 8 RHpOME, is formed by two closely related enzymes, linoleate diol synthases (LDS) and linoleate 10 R -dioxygenases (10 R -DOX). These enzymes belong to the group of animal heme peroxidases/myeloperoxidases that also include cyclooxygenases (COX) of animals and ␣ -DOX of plants ( 15, 16 ).Abstract Seven Z -octadecenoic acids having the double bond located in positions 6Z to 13Z were photooxidized. The resulting hydroperoxy-E -octadecenoic acids [HpOME( E )] were resolved by chiral phase-HPLC-MS, and the absolute confi gurations of the enantiomers were determined by gas chromatographic analysis of diastereoisomeric derivatives. The MS/MS/MS spectra showed characteristic fragments, which were infl uenced by the distance between the hydroperoxide and carboxyl groups. These fatty acids were then investigated as substrates of cyclooxygenase-1 (COX-1), manganese lipoxygenase (