Macrolide Stereochemistry. III. A Configurational Model for Macrolide Antibiotics<sup>1</sup>

Celmer, Walter D.

doi:10.1021/ja01086a038

Cited by 82 publications

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“…28 At this scale, each enzyme incubation can be carried out in a convenient volume of 500 μL, using [10][11][12][13][14][15][16][17][18][19][20] …”

Section: Gc-ms Analysis Of Triketide Lactone Diastereomersmentioning

confidence: 99%

“…More than 40 years ago, Celmer pointed out the intriguing structural and stereochemical homology among a large number of 12-, 14-, and 16-membered macrolides, which could be summarized by a single stereochemical model. 12 Since that time, the Celmer Model has provided a frame of reference for numerous investigations of the stereochemistry of macrolide biosynthesis. Although the modular organization of the DEBS PKS accounts in clear and elegant fashion for the observed pattern of substitution and oxidation in erythromycin and related macrolides, the detailed biochemical basis for the complex stereochemistry of the parent 6-dEB macrolide aglycone remains to be resolved.…”

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confidence: 99%

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Stereospecificity of Ketoreductase Domains of the 6-Deoxyerythronolide B Synthase

Castonguay

Chen

et al. 2007

J. Am. Chem. Soc.

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Abstract6-Deoxyerythronolide B synthase (DEBS) is a modular polyketide synthase (PKS) responsible for the biosynthesis of 6-dEB (1), the parent aglycone of the broad spectrum macrolide antibiotic erythromycin. Individual DEBS modules, which contain the catalytic domains necessary for each step of polyketide chain elongation and chemical modification, can be deconstructed into constituent domains. To better understand the intrinsic stereospecificity of the ketoreductase (KR) domains, an in vitro reconstituted system has been developed involving combinations of ketosynthase (KS) -acyl transferase (AT) didomains with acyl-carrier protein (ACP) and KR domains from different DEBS modules. Incubations with (2S,3R)-2-methyl-3-hydroxypentanoic acid N-acetylcysteamine thioester (2) and methylmalonyl-CoA plus NADPH result in formation of a reduced, ACP-bound triketide that is converted to the corresponding triketide lactone 4 by either base-or enzyme-catalyzed hydrolysis/cyclization. A sensitive and robust GC-mass spectrometry technique has been developed to assign the stereochemistry of the resulting triketide lactones, on the basis of direct comparison with synthetic standards of each of the four possible diasteromers 4a-4d. Using the [KS][AT] didomains from either DEBS module 3 or module 6 in combination with KR domains from modules 2 or 6 gave in all cases exclusively (2R,3S,4R,5R)-3,5-dihydroxy-2,4-dimethyl-n-heptanoic acid-δ-lactone (4a). The same product was also generated by a chimeric module in which [KS3][AT3] was fused to [KR5][ACP5] and the DEBS thioesterase [TE] domain. Reductive quenching of the ACPbound 2-methyl-3-ketoacyl triketide intermediate with sodium borohydride confirmed that in each case the triketide intermediate carried only an unepimerized D-2-methyl group. The results confirm the predicted stereospecificity of the individual KR domains, while revealing an unexpected configurational stability of the ACP-bound 2-methyl-3-ketoacyl thioester intermediate. The methodology should be applicable to the study of any combination of heterologous [KS][AT] and [KR] domains.Modular polyketide synthases (PKSs) are multifunctional enzymes responsible for the biosynthesis of polyketides metabolites that exhibit a wide range of important biological properties, including antibacterial, antifungal, anticancer, and immunosuppressive activity. 1 They catalyze repetitive Claisen-like condensations between methylmalonyl or malonyl thioester building blocks and the growing polyketide acyl thioesters. Using an assembly line of active sites, each module is responsible for one cycle of polyketide chain elongation and *To whom correspondence should be addressed. E-mail: David_Cane@brown.edu. (TE) domain, located at the C-terminus of the furthest downstream module, catalyzes release and concomitant cyclization of the mature, full-length macrocyclic polyketide. NIH Public AccessThe 6-deoxyerythronolide synthase (DEBS) from Saccharopolyspora erythraea, which is by far the most thoroughly studied modular PKS, is responsib...

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“…28 At this scale, each enzyme incubation can be carried out in a convenient volume of 500 μL, using [10][11][12][13][14][15][16][17][18][19][20] …”

Section: Gc-ms Analysis Of Triketide Lactone Diastereomersmentioning

confidence: 99%

mentioning

confidence: 99%

Stereospecificity of Ketoreductase Domains of the 6-Deoxyerythronolide B Synthase

Castonguay

Chen

et al. 2007

J. Am. Chem. Soc.

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“…16 The studies revealed that these metabolites arose from condensation of propionate-derived units similar to the biosynthesis of macrolide 17 and polyether antibiotics. 18 Some years later,…”

Section: Biosynthesismentioning

confidence: 99%

“…After stirring at 40 °C for 1 day, the mixture was diluted with ethyl acetate, washed sequentially with 1% aq citric acid (x3), saturated aq NaHCO 3 and brine, dried over Na 2 SO 4 , concentrated, and fractionated by FCC (5% diethyl ether in hexanes) to yield the titled compound (62 mg, 14%; dr [16][17][18] and recovered ent-10-epi-167 (338 mg, 80%; dr [16][17][18]. The latter fraction was re-subjected to the isomerization conditions and after a total of six isomerization cycles, recovered ent-10-epi-167 (119 mg, 28%; dr [16][17][18] (q, CH 3 C-8'), 12.7 (q, CH 3 C-10'), 7.9 (q, CH 3 C-9'), 7.5 (q, C-3), 6.4 (q, CH 3 CC-3'), 2.2 (q ×3, 29.6 (t, CH 2 C-3'), 27.4 (t, C-4), 13.5 (q, CH 3 C-8'), 12.6 (q, CH 3 C-10'), 10.7 (q, C-5), 7.9 (q, CH 3 C-9'), 6.5 (q, CH 3 CC-3'), 4.5 (q, C-1), 2.2 (q ×3, CH 3 …”

Section: Ent-167mentioning

confidence: 99%

On the Origin of Siphonariid Polypropionates: Total Synthesis of Caloundrin B and Its Isomerization to Siphonarin B

Becerril-Jiménez

Ward

2012

Org. Lett.

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Enantioselective synthesis of the enantiomer of caloundrin B was achieved by strategic aldol coupling of an enantiopure trioxaadamantanecontaining ketone with a racemic pyrone-containing aldehyde via kinetic resolution. In the presence of imidazole, ent-caloundrin B is cleanly isomerized to ent-siphonarin B confirming the proposed structure and absolute configuration for caloundrin B and establishing that it is a plausible biosynthetic product from which siphonarin B and baconipyrones A and C can originate.

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“…8 The structures of all known members of these 18-membered macrolides are presented in Figure 1. It should be noted that the absolute stereochemistry is only known for tiacumicin B, and, given the Celmer model for the stereochemistry of macrolides, 9 it has been assumed that this will be the same throughout the macrolide ring, except that no such assumption applied for the exocyclic position C-18. Given this assumption, it would appear that lipiarmycin A3, clostomicin B 1 and tiacumicin B were identical and among the most active against C. difficile.…”

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confidence: 99%

The ups and downs of drug discovery: the early history of Fidaxomicin

McAlpine¹

2017

J Antibiot

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Macrolide Stereochemistry. III. A Configurational Model for Macrolide Antibiotics¹

Cited by 82 publications

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Stereospecificity of Ketoreductase Domains of the 6-Deoxyerythronolide B Synthase

Stereospecificity of Ketoreductase Domains of the 6-Deoxyerythronolide B Synthase

On the Origin of Siphonariid Polypropionates: Total Synthesis of Caloundrin B and Its Isomerization to Siphonarin B

The ups and downs of drug discovery: the early history of Fidaxomicin

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Macrolide Stereochemistry. III. A Configurational Model for Macrolide Antibiotics1

Cited by 82 publications

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Stereospecificity of Ketoreductase Domains of the 6-Deoxyerythronolide B Synthase

Stereospecificity of Ketoreductase Domains of the 6-Deoxyerythronolide B Synthase

On the Origin of Siphonariid Polypropionates: Total Synthesis of Caloundrin B and Its Isomerization to Siphonarin B

The ups and downs of drug discovery: the early history of Fidaxomicin

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Macrolide Stereochemistry. III. A Configurational Model for Macrolide Antibiotics¹