The S-n-propyl analogue of S-adenosylmethionine

Schlenk, F.; Dainko, J. L.

doi:10.1016/0304-4165(75)90359-1

Cited by 28 publications

(16 citation statements)

References 32 publications

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“…Although AdoMet is the natural substrate for many enzymatic methylations, a number of methyltransferases have been shown to be capable of transferring non-natural alkyl, alkenyl, or alkynyl group through the substitution of AdoMet with the corresponding S-alkyl, S-akenyl, and S-alkynyl analogs (44,45). Preliminary investigation with S-ethyl and S-n-propyl analogs of AdoMet indeed demonstrated that NcsB1 can turnover 2,7-dihydroxy-5-methyl-1-naphthoic acid (8) into the corresponding 7-ethyl ether and 7-n-propyl ether, respectively, the identities of which have been confirmed by high resolution ESI-MS.…”

Section: Discussionmentioning

confidence: 99%

Regiospecific O-Methylation of Naphthoic Acids Catalyzed by NcsB1, an O-Methyltransferase Involved in the Biosynthesis of the Enediyne Antitumor Antibiotic Neocarzinostatin

Luo

Lin

Zhang

et al. 2008

Journal of Biological Chemistry

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Neocarzinostatin, a clinical anticancer drug, is the archetypal member of the chromoprotein family of enediyne antitumor antibiotics that are composed of a nonprotein chromophore and an apoprotein. The neocarzinostatin chromophore consists of a nine-membered enediyne core, a deoxyaminosugar, and a naphthoic acid moiety. We have previously cloned and sequenced the neocarzinostatin biosynthetic gene cluster and proposed that the biosynthesis of the naphthoic acid moiety and its incorporation into the neocarzinostatin chromophore are catalyzed by five enzymes NcsB, NcsB1, NcsB2, NcsB3, and NcsB4. Here we report the biochemical characterization of NcsB1, unveiling that: (i) NcsB1 is an S-adenosyl-L-methionine-dependent O-methyltransferase; (ii) NcsB1 catalyzes regiospecific methylation at the 7-hydroxy group of its native substrate, 2,7-dihydroxy-5-methyl-1-naphthoic acid; (iii) NcsB1 also recognizes other dihydroxynaphthoic acids as substrates and catalyzes regiospecific O-methylation; and (iv) the carboxylate and its ortho-hydroxy groups of the substrate appear to be crucial for NcsB1 substrate recognition and binding, and O-methylation takes place only at the free hydroxy group of these dihydroxynaphthoic acids. These findings establish that NcsB1 catalyzes the third step in the biosynthesis of the naphthoic acid moiety of the neocarzinostatin chromophore and further support the early proposal for the biosynthesis of the naphthoic acid and its incorporation into the neocarzinostatin chromophore with free naphthoic acids serving as intermediates. NcsB1 represents another opportunity that can now be exploited to produce novel neocarzinostatin analogs by engineering neocarzinostatin biosynthesis or applying directed biosynthesis strategies. Neocarzinostatin (NCS),3 a clinical anticancer drug used to treat leukemia and cancers of the bladder, stomach, pancreas, liver, and brain, is an archetypal member of the chromoprotein family of enediyene antitumor antibiotics that are composed of a nonprotein chromophore and an apoprotein (1-3). NCS was originally isolated from Streptomyces carzinostaticus in 1965 (1-3). Its apoprotein NcsA is encoded by the ncsA gene and protects, carries, and delivers the reactive NCS chromophore (4). The NCS chromophore (1, Fig. 1B) is composed of a ninemembered enediyne core, a deoxyaminosugar, and a naphthoic acid moiety (2, 5). As a member of the enediyne family, the biological activity of NCS is derived from its ability to cleave DNA (6). The NCS chromophore undergoes Myers-Saito cycloaromatization to form a 2,6-indacene diradical species that subsequently abstracts hydrogen atoms from the deoxyribose of DNA, leading to single-and double-stranded DNA breaks (2, 7). For NCS, a thiol is often required to trigger the cycloaromatization, although a few enediynes have been reported to form diradicals via the cycloaromatization in a thiol-independent manner, likely the result of the intrinsic reactivity of the nine-membered ring enediyne core (1, 2, 7). The mechanism of action for NCS also invo...

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Section: Discussionmentioning

confidence: 99%

Regiospecific O-Methylation of Naphthoic Acids Catalyzed by NcsB1, an O-Methyltransferase Involved in the Biosynthesis of the Enediyne Antitumor Antibiotic Neocarzinostatin

Luo

Lin

Zhang

et al. 2008

Journal of Biological Chemistry

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“…Although DNA and RNA methyltransferases are able to use synthetic S-adenosylmethionine analogues with extended carbon chains both in vitro and in vivo (Schlenk & Dainko, 1975;Klimasauskas & Weinhold, 2007;Motorin et al, 2011), there do not appear to be any reports indicating that DNA or RNA methyltransferases actually use such analogues in vivo for the modification of nucleic acids. We hope that our findings will lead to further characterization of the function and mechanism of CmoA and its SCM-SAH cofactor.…”

Section: Discussionmentioning

confidence: 99%

S-Adenosyl-S-carboxymethyl-L-homocysteine: a novel cofactor found in the putative tRNA-modifying enzyme CmoA

Byrne

Whelan

Aller

et al. 2013

Acta Crystallogr D Biol Cryst

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Uridine at position 34 of bacterial transfer RNAs is commonly modified to uridine-5-oxyacetic acid (cmo 5 U) to increase the decoding capacity. The protein CmoA is involved in the formation of cmo 5 U and was annotated as an S-adenosyl-lmethionine-dependent (SAM-dependent) methyltransferase on the basis of its sequence homology to other SAMcontaining enzymes. However, both the crystal structure of Escherichia coli CmoA at 1.73 Å resolution and mass spectrometry demonstrate that it contains a novel cofactor, S-adenosyl-S-carboxymethyl-l-homocysteine (SCM-SAH), in which the donor methyl group is substituted by a carboxymethyl group. The carboxyl moiety forms a salt-bridge interaction with Arg199 that is conserved in a large group of CmoA-related proteins but is not conserved in other SAMcontaining enzymes. This raises the possibility that a number of enzymes that have previously been annotated as SAMdependent are in fact SCM-SAH-dependent. Indeed, inspection of electron density for one such enzyme with known X-ray structure, PDB entry 1im8, suggests that the active site contains SCM-SAH and not SAM.

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“…Slight response to other homologs of methionine has been observed by Stekol (IOO), but the products have not been isolated. With a special strain of Saccharomyces cerevisiae, S-adenosylS-n-propyl-L-homocysteine (the n-propyl analog of AdoMet) has been obtained and characterized (81). 5'-Deoxy-5'8-n-propylthioadenosine has been produced from this by hydrolysis, but the low yields of the parent sulfonium compound make the procedure impractical as compared with organic sythesis.…”

Section: Biosynthesismentioning

confidence: 98%

“…Dowex-50, H ' , 100-200 mesh size, retains the nucleoside firmly; on elution with an acid gradient of HCI ranging from 0.5 to 4 N , methionine and homoserine or its lactone precede MTA (<1 N); about 1.5 N acid releases MTA, while AdoMet requires 3 N acid for elution. With short columns, adenine and S-adenosylhomocysteine may overlap with MTA (81). Dowex 50, Na+, can be used for the separation of MTA, adenosylhomocysteine, and adenine from AdoMet; only the latter is retained (43).…”

Section: Ion Exchange Chromatographymentioning

confidence: 99%