Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 2. Modification of the base portion of S-adenosylhomocysteine

Borchardt, Ronald T.; Huber, J. A.; Wu, Yih Shiong

doi:10.1021/jm00254a017

Cited by 65 publications

(44 citation statements)

References 8 publications

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“…52,[57][58][59][60][61][62][63][64] These broad-spectrum methyltransferase inhibitors were found to also block viral mRNA methyltransferases, which are critical for translation of viral proteins in infected cells. Ron's 1980 publication of a Perspective article in the Journal of Medicinal Chemistry on AdoMet-dependent methyltransferases as potential therapeutic targets 65 established him as a broad thinker in this important area of investigation and directly inspired a young graduate student (now-Professor Michael Wolfe) in the Department of Medicinal Chemistry at KU to join Ron's research group to do the research for his Ph.D. dissertation.…”

Section: Transmethylation and S-adenosyl-l-homocysteine Hydrolasementioning

confidence: 99%

A Tribute to Ronald T. Borchardt—Teacher, Mentor, Scientist, Colleague, Leader, Friend, and Family Man

Schowen

Borchardt

et al. 2016

Journal of Pharmaceutical Sciences

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Section: Transmethylation and S-adenosyl-l-homocysteine Hydrolasementioning

confidence: 99%

A Tribute to Ronald T. Borchardt—Teacher, Mentor, Scientist, Colleague, Leader, Friend, and Family Man

Schowen

Borchardt

et al. 2016

Journal of Pharmaceutical Sciences

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“…The hydrogen peroxide oxidation of AdoHcy (2) leads to the sulfoxide analogue 37 (Figure 9.1), which can be regarded as an isostere of AdoMet (1) [119,120]. The sulfoxide analogue 37 is typically obtained in an approximately 1 : 1 diastereomeric mixture at sulfur, and the diastereoisomers have been separated by using reversedphase HPLC [121].…”

Section: Sulfoxide and Sulfone Analogues Of Adometmentioning

confidence: 99%

“…The sulfoxide analogue 37 is typically obtained in an approximately 1 : 1 diastereomeric mixture at sulfur, and the diastereoisomers have been separated by using reversedphase HPLC [121]. Stronger oxidation conditions lead to the sulfone analogue 38 (Figure 9.1) [120,121]. Both AdoMet analogues show a moderate inhibitory effect on AdoMet-dependent enzymes such as MTases [122][123][124], ACC synthase [125], and CFA synthase [121], although in all cases AdoHcy (2) was the stronger inhibitor.…”

Section: Sulfoxide and Sulfone Analogues Of Adometmentioning

confidence: 99%

“…This charge recognition also explains why AdoHcy (2), though missing a positive charge at sulfur, has a much lower binding affinity. In this respect it is interesting to note that, for most MTases, AdoHcy (2) is a strong product inhibitor [120] and that the positive charge on sulfur of AdoMet (1) is apparently less well-recognized by the enzymes. This is line with the catalytic role of the enzymes, because stabilization of the positive charge is expected to make AdoMet (1) less reactive.…”

Section: Sulfoxide and Sulfone Analogues Of Adometmentioning

confidence: 99%

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S‐Adenosyl‐L‐Methionine and Related Compounds

Dalhoff¹,

Weinhold

2008

Modified Nucleosides

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The sulfonium compound S-adenosyl-L-methionine (AdoMet, also known as SAM or SAMe, 1) is one of the most versatile biomolecules in nature and one of the most widely used enzyme substrates, second perhaps only to adenosine triphosphate (ATP) (Schemes 9.1 and 9.2). AdoMet (1) may be found in all phyla of life, and is one of the molecules crucial for the existence of living organisms. First identified by Cantoni in 1953 [1, 2] as the active methyl donor formed from L-methionine and ATP, AdoMet (1) proved to be not only the major methyl donor in nature but also to be involved in many other metabolic reactions [3,4]. The versatility of the cofactor is based on the reactivity of the pivotal sulfonium center, which activates the adjacent carbon atoms for nucleophilic attack, deprotonation, and radical formation. This leads to a unique cofactor in which all constituents are used in biochemical reactions. The group transfer reactions result in the release of one of three different thioether products which are more stable than the sulfonium compound, and thereby providing the driving force for these enzyme-catalyzed reactions. These highly preferable thermodynamics of AdoMet-dependent transfer reactions result in a strong preference for this cofactor compared, for example, to other methyl donors such as N5-methyltetrahydrofolate. Due to the electron lone pair in addition to the three different substituents, the sulfonium group is chiral, and the naturally occurring AdoMet (1) is S-configured at sulfur [5].Many other naturally occurring alkylated thioadenosines are derived from AdoMet (1) such as S-adenosyl-L-homocysteine (AdoHcy, also called SAH, 2) and 5 0 -deoxy-5 0 -methylthioadenosine (MTA, 3) (Scheme 9.3), although these compounds and their related 5 0 -thioethers are beyond the scope of this chapter. AdoMet (1) and its derivatives are involved in key metabolic reactions, cell cycle regulation and the storage of epigenetic information, which makes them not only highly interesting for studying biological pathways but also as in-vitro or in-vivo biochemical tools and candidates for diagnostics and therapeutics.

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“…), which corresponds to previously reported values for InoHcy (10; Y. S. Wu, Ph.D. thesis, University of Kansas, Lawrence, 1975). The NMR spectrum was determined by using a G. E. QE 300-MHz NMR spectrometer from 4.7 mg of the sample in D20: 8 8.29, 8.17 (2s, 2H, C8-H, C2-H), 6.05 (d, 1H, J = 5.0, C1l-H), 4.40 (m, 1H, C3.-H, collapsed to a doublet upon irradiation at 4.30), 4.30 (m, 1H, C4 -H, collapsed to a doublet upon irradiation at 3.00), 3.79 (t, 1H, J = 6.9, C',-H, collapsed to a singlet upon irradiation at 2.08), 3.00 (pair of overlapping AB patterns, 2H, Jgem = 14 Hz, C5-H2), 2.67 (t, 2H, J = 7.6, C,-H2, collapsed to a singlet upon irradiation at 2.08), 2.08 (m, 2H, Jat13 = 6.9, J13y = 7.5, C.-H2 …”

mentioning

confidence: 99%

S-adenosylhomocysteine metabolism in Streptomyces flocculus

Speedie

Zulty

1988

J Bacteriol

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S-Adenosylhomocysteine metabolism was studied in cell extracts of streptonigrin-producing Streptomyces flocculus. The major route of metabolism was found to be deamination to form S-inosylhomocysteine. The metabolite was purified by high-performance liquid chromatography and identified by its UV and nuclear magnetic resonance spectra and by its chemical degradation to hypoxanthine.Streptomyces flocculus (ATCC 13257) produces the antitumor antibiotic streptonigrin (9). The biosynthetic pathway which yields streptonigrin involves an S-adenosylmethionine-mediated C-methylation of the I position of the side chain of tryptophan to form P-methyltryptophan (7), as well as two 0-methylations later in the pathway (6). The tryptophan C-methyltransferase is the first enzyme in the pathway which commits a primary metabolite to antibiotic biosynthesis and therefore is a likely site of regulation for the pathway. One product of the reaction, S-adenosyl-L-homocysteine (AdoHcy), is known to be a potent inhibitor of S-adenosylmethionine-dependent methyltransferases (2, 4), and inhibition of the tryptophan C-methyltransferase by AdoHcy has been demonstrated in partially purified enzyme preparations (M. K. Speedie and B. Fox, unpublished data).Cellular levels of AdoHcy are known to be regulated in eucaryotic cells by AdoHcy hydrolase (EC 3.3.1.1), which hydrolyzes AdoHcy to adenosine and homocysteine (12). In procaryotic organisms, the predominant route of metabolism is catalyzed by AdoHcy nucleosidase (EC 3.2.2.9), which generates adenine and S-ribosylhomocysteine (14), although recently Shimizu et al. (12) demonstrated the occurrence of AdoHcy hydrolase in some procaryotic organisms, including one streptomycete. In order to examine AdoHcy metabolism in S. flocculus, we incubated cell extract with AdoHcy and discovered an unexpected metabolite, S-inosylhomocysteine (InoHcy), as the major product. The identification of this metabolite is the subject of this report.Cultures of S. flocculus (ATCC 13257) were inoculated with a 5% inoculum of seed culture which had been grown for 48 h from a spore suspension in 100 ml of Emerson broth (1.0% glucose, 0.4% beef extract, 0.4% Gelysate peptone, 0.1% yeast extract, 0.25% NaCl in 1 liter of distilled water, adjusted to pH 7.0) in a 1-liter Erlenmeyer flask at 28°C and 180 rpm. Cultures (250 ml of Emerson broth in 2-liter Erlenmeyer flasks) were grown for 24 h at 28°C and 180 rpm (New Brunswick model M52 Controlled Environment Incubator Shaker) and then harvested by filtration. A cell slurry in 10 mM sodium phosphate buffer (pH 8.0) with 1 mM dithiothreitol was sonified at setting 5 on an Ultrasonics sonifier in an ice bath and centrifuged for 20 min at 30,000 x g to remove cell debris. The crude cell extract was precipitated with 70% ammonium sulfate and centrifuged at 30,000 x g for 20 min at 6°C. The precipitate was redissolved in 20 mM potassium phosphate buffer, pH 7.0, and dialyzed for 24 * Corresponding author. h against two changes (2.5 liters) of the same buffer at 4°C. This prepar...

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Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 2. Modification of the base portion of S-adenosylhomocysteine

Cited by 65 publications

References 8 publications

A Tribute to Ronald T. Borchardt—Teacher, Mentor, Scientist, Colleague, Leader, Friend, and Family Man

A Tribute to Ronald T. Borchardt—Teacher, Mentor, Scientist, Colleague, Leader, Friend, and Family Man

S‐Adenosyl‐L‐Methionine and Related Compounds

S-adenosylhomocysteine metabolism in Streptomyces flocculus

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