Posted by desolationrower on March 11, 2009, at 0:35:38
i was looking at the tca/cancer thing, and noticed MAOIs seem to have slightly lower cancer than baseline
i found this, then
trans-2-Phenylcyclopropylamine Is a Mechanism-Based Inactivator of the Histone Demethylase LSD1The catalytic domain of the flavin-dependent human histone demethylase lysine-specific demethylase 1 (LSD1) belongs to the family of amine oxidases including polyamine oxidase and monoamine oxidase (MAO). We previously assessed monoamine oxidase inhibitors (MAOIs) for their ability to inhibit the reaction catalyzed by LSD1 [Lee, M. G., et al. (2006) Chem. Biol. 13, 563−567], demonstrating that trans-2-phenylcyclopropylamine (2-PCPA, tranylcypromine, Parnate) was the most potent with respect to LSD1. Here we show that 2-PCPA is a time-dependent, mechanism-based irreversible inhibitor of LSD1 with a KI of 242 μM and a kinact of 0.0106 s-1. 2-PCPA shows limited selectivity for human MAOs versus LSD1, with kinact/KI values only 16-fold and 2.4-fold higher for MAO B and MAO A, respectively. Profiles of LSD1 activity and inactivation by 2-PCPA as a function of pH are consistent with a mechanism of inactivation dependent upon enzyme catalysis. Mass spectrometry supports a role for FAD as the site of covalent modification by 2-PCPA. These results will provide a foundation for the design of cyclopropylamine-based inhibitors that are selective for LSD1 to probe its role in vivo.
p53 is regulated by the lysine demethylase LSD1.
Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T, Berger SL.The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation. Histone lysine methylation has recently been shown to be reversible; however, it is not known whether non-histone proteins are substrates for demethylation. Here we show that, in human cells, the histone lysine-specific demethylase LSD1 (refs 3, 4) interacts with p53 to repress p53-mediated transcriptional activation and to inhibit the role of p53 in promoting apoptosis. We find that, in vitro, LSD1 removes both monomethylation (K370me1) and dimethylation (K370me2) at K370, a previously identified Smyd2-dependent monomethylation site. However, in vivo, LSD1 shows a strong preference to reverse K370me2, which is performed by a distinct, but unknown, methyltransferase. Our results indicate that K370me2 has a different role in regulating p53 from that of K370me1: K370me1 represses p53 function, whereas K370me2 promotes association with the coactivator 53BP1 (p53-binding protein 1) through tandem Tudor domains in 53BP1. Further, LSD1 represses p53 function through the inhibition of interaction of p53 with 53BP1. These observations show that p53 is dynamically regulated by lysine methylation and demethylation and that the methylation status at a single lysine residue confers distinct regulatory output. Lysine methylation therefore provides similar regulatory complexity for non-histone proteins and for histones.
->p53 is anticarcinogenic, usually seen as a good thing. health effect?
of course if this sounds familiar remember this study
Pharmacogenetic Analysis of Lithium-induced Delayed Aging in Caenorhabditis elegans*Formula
Gawain McColl, Supported by the American Federation for Aging Research{ddagger}1, David W. Killilea§, Alan E. Hubbard¶, Maithili C. Vantipalli{ddagger}, Simon Melov{ddagger}2, and Gordon J. Lithgow{ddagger}3From the {ddagger}Buck Institute for Age Research, Novato, California 94945, the §Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, California 94609, and the ¶School of Public Health, University of California, Berkeley California 94720
Lithium (Li+) has been used to treat mood affect disorders, including bipolar, for decades. This drug is neuroprotective and has several identified molecular targets. However, it has a narrow therapeutic range and the one or more underlying mechanisms of its therapeutic action are not understood. Here we describe a pharmacogenetic study of Li+ in the nematode Caenorhabditis elegans. Exposure to Li+ at clinically relevant concentrations throughout adulthood increases survival during normal aging (up to 46% median increase). Longevity is extended via a novel mechanism with altered expression of genes encoding nucleosome-associated functions. Li+ treatment results in reduced expression of the worm ortholog of LSD-1 (T08D10.2), a histone demethylase; knockdown by RNA interference of T08D10.2 is sufficient to extend longevity (~25% median increase), suggesting Li+ regulates survival by modulating histone methylation and chromatin structure.
-d/r
poster:desolationrower
thread:884820
URL: http://www.dr-bob.org/babble/neuro/20090129/msgs/884820.html