Design, Synthesis, and Evaluation of a Depsipeptide Mimic of Tendamistat

Sefler, Andrea M.; Kozlowski, Marisa C.; Guo, Tao; Bartlett, Paul A.

doi:10.1021/jo9616062

Cited by 40 publications

(28 citation statements)

References 48 publications

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“…D-2-Hydroxyglutarate (disodium salt) and 3-phospho-D-glycerate were from Sigma-Aldrich. S-5-Amino-2-hydroxyvalerate and R-5-amino-2-hydroxyvalerate were synthesized from L-ornithine and D-ornithine ⅐ HCl (Sigma-Aldrich, St. Louis, MO) by following a previously published procedure (31).…”

Section: Methodsmentioning

confidence: 99%

Identification ofEscherichia coliYgaF as anl-2-Hydroxyglutarate Oxidase

Kalliri¹,

Mulrooney²,

Hausinger

2008

J Bacteriol

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YgaF, a protein of previously unknown function in Escherichia coli, was shown to possess noncovalently bound flavin adenine dinucleotide and to exhibit L-2-hydroxyglutarate oxidase activity. The inability of anaerobic, reduced enzyme to reverse the reaction by reducing the product ␣-ketoglutaric acid is explained by the very high reduction potential (؉19 mV) of the bound cofactor. The likely role of this enzyme in the cell is to recover ␣-ketoglutarate mistakenly reduced by other enzymes or formed during growth on propionate. On the basis of the identified function, we propose that this gene be renamed lhgO.The ygaF gene of Escherichia coli is located immediately downstream of csiD, which encodes a crystallographically characterized protein of unknown function (4), and just upstream of the gabDTP operon and csiR, which encode succinic semialdehyde dehydrogenase, ␥-aminobutyric acid (GABA) transaminase, a GABA-specific permease, and a repressor (Fig. 1). The first five genes, and perhaps all six (30), are coregulated by CsiR repression and cyclic AMP-cyclic AMP receptor protein and s induction acting at csiD p during carbon starvation and at stationary phase (14,18). Expression of gabDTP is additionally controlled by s binding to gabD p1 , which is triggered by multiple-stress induction (18), and by Nac/ 70 interaction with gabD p2 in response to nitrogen starvation (30). YgaF is not obviously involved in GABA metabolism (30), and its role is unknown.On the basis of its amino acid sequence, YgaF is likely to be a flavoenzyme. It has been estimated that 1 to 3% of the identified proteins in prokaryotic and eukaryotic cells contain flavin (5) and these abundant enzymes catalyze a wide range of reactions with a diverse set of substrates, including alcohols, aldehydes, ketones, amines, dithiols, amino acids, and hydroxy acids (34). Most of these enzymes transition between the fully oxidized and two-electron reduced forms of their cofactor, but in some cases, the one-electron reduced semiquinone species is stabilized. Reoxidation of the reduced flavin coenzyme can take place via several processes, including the reaction with oxygen, as in the case of flavin oxidases. The flavin cofactors (generally, flavin mononucleotide [FMN] or flavin adenine dinucleotide [FAD]) often are tightly bound to these enzymes, and in selected examples, the coenzyme is covalently attached to the protein (11). Sequence comparisons of YgaF reveal this 422-amino-acid E. coli protein to be homologous to human mitochondrial L-2-hydroxyglutarate dehydrogenase (41% identity over 398 residues) (28), Helicobacter pylori malate:quinone oxidoreductase (24% identity over 421 residues) (33), Bacillus sp. strain B-0618 creatinase and sarcosine oxidase (23% identity over 255 residues) (32), human mitochondrial dimethylglycine dehydrogenase (24% identity over 227 residues) (2), Bacillus subtilis glycine oxidase (25% identity over 146 residues) (9), human peroxisomal L-pipecolic acid oxidase (21% identity over 219 residues) (6), and many other flavoenzymes...

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Section: Methodsmentioning

confidence: 99%

Identification ofEscherichia coliYgaF as anl-2-Hydroxyglutarate Oxidase

Kalliri¹,

Mulrooney²,

Hausinger

2008

J Bacteriol

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“…Several successful cyclizations via ester bond formation (lactonization) have been reported [1][2][3], but ring closure via formation of an amide bond (lactamization) [4][5][6] is usually easier and therefore preferred [7].…”

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confidence: 99%

Synthesis of Enniatin‐like Cyclic Depsipeptides via ‘Direct Amide Cyclization’

Köttgen

Linden

Heimgartner

2006

Helvetica Chimica Acta

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The synthesis of several 18-membered cyclodepsipeptides with an alternating sequence of a,adisubstituted a-amino acids and a-hydroxy acids (compounds 14a-14e) is described. The ring closure via macrolactonization was accomplished by treatment of a diluted suspension of the corresponding linear precursors 12a-12e in toluene with HCl gas, i.e., the so-called 'direct amide cyclization'. The incorporation of the a,a-disubstituted a-amino acids was achieved via the 'azirine/oxazolone method' with 2H-azirin-3-amines of type 6 and 9 as building blocks. The structure of the cyclic depsipeptide 14a was established by X-ray crystallography.

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“…With required fragment 3 in hand, we proceeded with the synthesis of topsentolide B 3 (Scheme 3). Thus, condensation of alcohol 3 with 5-hexenoic acid by using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI)/4-(dimethylamino)pyridine (DMAP) in pyridine [15,3] afforded ester 15, and subsequent deprotection of the acetonide with (-)-camphor-10-sulfonic acid in methanol afforded desired product 2. The final step of our synthetic plan involved the generation of the lactone ring by Grubbs RCM.…”

Section: Resultsmentioning

confidence: 99%