Glycosyltransferases involved in the biosynthesis of bacterial secondary metabolites may be useful for the generation of sugar-modified analogues of bioactive natural products. Some glycosyltransferases have relaxed substrate specificity, and it has been assumed that promiscuity is a feature of the class. As part of a program to explore the synthetic utility of these enzymes, we have analyzed the substrate selectivity of glycosyltransferases that attach similar 2-deoxy-L-sugars to glycopeptide aglycons of the vancomycin-type, using purified enzymes and chemically synthesized TDP beta-2-deoxy-L-sugar analogues. We show that while some of these glycopeptide glycosyltransferases are promiscuous, others tolerate only minor modifications in the substrates they will handle. For example, the glycosyltransferases GtfC and GtfD, which transfer 4-epi-L-vancosamine and L-vancosamine to C-2 of the glucose unit of vancomycin pseudoaglycon and chloroorienticin B, respectively, show moderately relaxed donor substrate specificities for the glycosylation of their natural aglycons. In contrast, GtfA, a transferase attaching 4-epi-L-vancosamine to a benzylic position, only utilizes donors that are closely related to its natural TDP sugar substrate. Our data also show that the spectrum of donors utilized by a given enzyme can depend on whether the natural acceptor or an analogue is used, and that GtfD is the most versatile enzyme for the synthesis of vancomycin analogues.

30 Mar 2004·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Characterization of a regiospecific epivancosaminyl transferase GtfA and enzymatic reconstitution of the antibiotic chloroeremomycin

Q1 · CROSS-FIELD

Article

Author: Walsh, Christopher T. ; Oberthür, Markus ; Tao, Junhua ; Kahne, Daniel ; Lu, Wei ; Leimkuhler, Catherine

Chloroeremomycin, a vancomycin family glycopeptide antibiotic has three sugars, one d -glucose and two l -4- epi -vancosamines, attached to the crosslinked heptapeptide backbone by three glycosyltransferases, GtfA, -B, and -C. Prior efforts have revealed that GtfB and -C in tandem build an epivancosaminyl-1,2-glucosyldisaccharide chain on residue 4 of the aglycone; however, the characterization of GtfA and glycosylation sequence of chloroeremomycin have been lacking. Here, we report the expression and purification of GtfA, as well as synthesis of its sugar donor, 2′-deoxy-thymidine 5′-diphosphate (dTDP)-β- l -4- epi -vancosamine. GtfA transfers 4- epi -vancosamine from the chemically synthesized dTDP-4- epi -vancosamine to the β-OH-Tyr 6 residue of the aglycone, preferentially after GtfB action, to generate chloroorienticin B. With the preferred kinetic order of GtfB, then GtfA, then GtfC established, we have succeeded in reconstitution of chloroeremomycin from the heptapeptide aglycone by the sequential actions of the three enzymes.

01 Nov 2002·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Novel semi-synthetic glycopeptide antibiotics active against methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE): doubly-modified water-soluble derivatives of chloroorienticin B

Q4 · MEDICINE

Article

Author: Yasuhiro Nishitani ; Tadashi Munekage ; Tatsuro Yasukata ; Yukitoshi Narukawa ; Yukihito Sumino ; Osamu Yoshida

A series of N-alkylated and aminomethylated derivatives of chloroorienticin B, a vancomycin-related glycopeptide antibiotic, were synthesized. Doubly-modified derivatives having both hydrophobic and hydrophilic substituents exhibited potent antibacterial activity against MRSA and VRE along with considerable water-solubility.

100 Deals associated with Chloroorienticin B

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


AACR2014	Not Applicable	Non-Small Cell Lung Cancer	-	Cucurbitacin B	dopmiadktx(zmgbzkwrum) = yvvazzfizp smpvsimncj (iafhwgqyrh )	Positive	01 Oct 2014
				Cucurbitacin B (Control (normal human bronchial epithelial cells))	lsgysqphzd(vvhkctyiqc) = qiyugbcaov cwzsrlqcjv (mjjmamjzrq )
AACR2010	Not Applicable	Breast Cancer	-	Cucurbitacin B	vswzsddiyf(rblgtpmquz) = rwnlylnwcb umpcwoqjzr (ihcvlqqism )	-	15 Apr 2010
				Dihydrocucurbitacin B	vswzsddiyf(rblgtpmquz) = jksrnxnfkh umpcwoqjzr (ihcvlqqism )

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