Novobiocin

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Novobiocin
Novobiocin2DCSD.svg
Novobiocin molecule spacefill.png
Clinical data
AHFS/Drugs.com International Drug Names
Routes of
administration 		intravenous
ATCvet code
Pharmacokinetic data
Bioavailability negligible oral bioavailability
Metabolism excreted unchanged
Elimination half-life 6 hours
Excretion renal
Identifiers
  • 4-Hydroxy-3-[4-hydroxy-3-(3-methylbut-2-enyl)benzamido]-8-methylcoumarin-7-yl 3-O-carbamoyl-5,5-di-C-methyl-α-L-lyxofuranoside
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.005.589 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C31H36N2O11
Molar mass 612.632 g·mol−1
3D model (JSmol)
Melting point 152 to 156 °C (306 to 313 °F) (dec.)
  • CC(C)=CCc1c(O)ccc(c1)C(=O)NC=2C(=O)Oc3c(C2O)ccc(c3C)O[C@@H]4OC(C)(C)[C@H](OC)[C@H]([C@H]4O)OC(=O)N
  • InChI=1S/C31H36N2O11/c1-14(2)7-8-16-13-17(9-11-19(16)34)27(37)33-21-22(35)18-10-12-20(15(3)24(18)42-28(21)38)41-29-23(36)25(43-30(32)39)26(40-6)31(4,5)44-29/h7,9-13,23,25-26,29,34-36H,8H2,1-6H3,(H2,32,39)(H,33,37)/t23-,25+,26-,29-/m1/s1 Yes check.svgY
  • Key:YJQPYGGHQPGBLI-KGSXXDOSSA-N Yes check.svgY
   (verify)

Novobiocin, also known as albamycin, is an aminocoumarin antibiotic that is produced by the actinomycete Streptomyces niveus , which has recently been identified as a subjective synonym for S. spheroides [1] a member of the class Actinomycetia. Other aminocoumarin antibiotics include clorobiocin and coumermycin A1. [2] Novobiocin was first reported in the mid-1950s (then called streptonivicin). [3] [4]

Contents

Clinical use

It is active against Staphylococcus epidermidis and may be used to differentiate it from the other coagulase-negative Staphylococcus saprophyticus , which is resistant to novobiocin, in culture.[ citation needed ]

Novobiocin was licensed for clinical use under the tradename Albamycin (Upjohn) in the 1960s. Its efficacy has been demonstrated in preclinical and clinical trials. [5] [6] The oral form of the drug has since been withdrawn from the market due to lack of efficacy. [7] A combination product of novobiocin and tetracycline, sold by Upjohn under brand names such as Panalba and Albamycin-T, was in particular the subject of intense FDA scrutiny before it was finally taken off the market. [8] [9] Novobiocin is an effective antistaphylococcal agent used in the treatment of MRSA. [10]

Mechanism of action

The molecular basis of action of novobiocin, and other related drugs clorobiocin and coumermycin A1 has been examined. [2] [11] [12] [13] [14] Aminocoumarins are very potent inhibitors of bacterial DNA gyrase and work by targeting the GyrB subunit of the enzyme involved in energy transduction. Novobiocin as well as the other aminocoumarin antibiotics act as competitive inhibitors of the ATPase reaction catalysed by GyrB. The potency of novobiocin is considerably higher than that of the fluoroquinolones that also target DNA gyrase, but at a different site on the enzyme. The GyrA subunit is involved in the DNA nicking and ligation activity.[ citation needed ]

Novobiocin has been shown to weakly inhibit the C-terminus of the eukaryotic Hsp90 protein (high micromolar IC50). Modification of the novobiocin scaffold has led to more selective Hsp90 inhibitors. [15] Novobiocin has also been shown to bind and activate the Gram-negative lipopolysaccharide transporter LptBFGC. [16] [17]

The ATP binding pocket of polymerase theta is blocked by novobiocin resulting in a loss of ATPase activity. This results in the loss of microhomology-mediated end joining as a pathway for homologous recombination deficient cells to circumvent DNA damaging agents. The action of novobiocin is syngeristic with PARP inhibitors for reducing tumor size in a mouse model. [18]

Structure

Novobiocin is an aminocoumarin. Novobiocin may be divided up into three entities; a benzoic acid derivative, a coumarin residue, and the sugar novobiose. [11] X-ray crystallographic studies have found that the drug-receptor complex of Novobiocin and DNA Gyrase shows that ATP and Novobiocin have overlapping binding sites on the gyrase molecule. [19] The overlap of the coumarin and ATP-binding sites is consistent with aminocoumarins being competitive inhibitors of the ATPase activity. [20]

Structure–activity relationship

In structure activity relationship experiments it was found that removal of the carbamoyl group located on the novobiose sugar lead to a dramatic decrease in inhibitory activity of novobiocin. [20]

Biosynthesis

This aminocoumarin antibiotic consists of three major substituents. The 3-dimethylallyl-4-hydroxybenzoic acid moiety, known as ring A, is derived from prephenate and dimethylallyl pyrophosphate. The aminocoumarin moiety, known as ring B, is derived from L-tyrosine. The final component of novobiocin is the sugar derivative L-noviose, known as ring C, which is derived from glucose-1-phosphate. The biosynthetic gene cluster for novobiocin was identified by Heide and coworkers in 1999 (published 2000) from Streptomyces spheroides NCIB 11891. [21] They identified 23 putative open reading frames (ORFs) and more than 11 other ORFs that may play a role in novobiocin biosynthesis.[ citation needed ]

The biosynthesis of ring A (see Fig. 1) begins with prephenate which is a derived from the shikimic acid biosynthetic pathway. The enzyme NovF catalyzes the decarboxylation of prephenate while simultaneously reducing nicotinamide adenine dinucleotide phosphate (NADP+) to produce NADPH. Following this NovQ catalyzes the electrophilic substitution of the phenyl ring with dimethylallyl pyrophosphate (DMAPP) otherwise known as prenylation. [22] DMAPP can come from either the mevalonic acid pathway or the deoxyxylulose biosynthetic pathway. Next the 3-dimethylallyl-4-hydroxybenzoate molecule is subjected to two oxidative decarboxylations by NovR and molecular oxygen. [23] NovR is a non-heme iron oxygenase with a unique bifunctional catalysis. In the first stage both oxygens are incorporated from the molecular oxygen while in the second step only one is incorporated as determined by isotope labeling studies. This completes the formation of ring A.

Figure 1. Biosynthetic scheme of benzamide portion of novobiocin (4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoic acid) Mandler NovoRevisions.tif
Figure 1. Biosynthetic scheme of benzamide portion of novobiocin (4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoic acid)

The biosynthesis of ring B (see Fig. 2) begins with the natural amino acid L-tyrosine. This is then adenylated and thioesterified onto the peptidyl carrier protein (PCP) of NovH by ATP and NovH itself. [24] NovI then further modifies this PCP bound molecule by oxidizing the β-position using NADPH and molecular oxygen. NovJ and NovK form a heterodimer of J2K2 which is the active form of this benzylic oxygenase. [25] This process uses NADP+ as a hydride acceptor in the oxidation of the β-alcohol. This ketone will prefer to exist in its enol tautomer in solution. Next a still unidentified protein catalyzes the selective oxidation of the benzene (as shown in Fig. 2). Upon oxidation this intermediate will spontaneously lactonize to form the aromatic ring B and lose NovH in the process.

Figure 2. Biosynthesis of 3-amino-4,7-dihydroxy-2H-chromen-2-one component of novobiocin (ring B) Novobiocin Ring B Synthesis.png
Figure 2. Biosynthesis of 3-amino-4,7-dihydroxy-2H-chromen-2-one component of novobiocin (ring B)

The biosynthesis of L-noviose (ring C) is shown in Fig. 3. This process starts from glucose-1-phosphate where NovV takes dTTP and replaces the phosphate group with a dTDP group. NovT then oxidizes the 4-hydroxy group using NAD+. NovT also accomplishes a dehydroxylation of the 6 position of the sugar. NovW then epimerizes the 3 position of the sugar. [26] The methylation of the 5 position is accomplished by NovU and S-adenosyl methionine (SAM). Finally NovS reduces the 4 position again to achieve epimerization of that position from the starting glucose-1-phosphate using NADH.

Figure 3. Biosynthesis of L-noviose component of novobiocin (ring C) L-Noviose Biosynthesis.png
Figure 3. Biosynthesis of L-noviose component of novobiocin (ring C)

Rings A, B, and C are coupled together and modified to give the finished novobiocin molecule. Rings A and B are coupled together by the enzyme NovL using ATP to diphosphorylate the carboxylate group of ring A so that the carbonyl can be attacked by the amine group on ring B. The resulting compound is methylated by NovO and SAM prior to glycosylation. [27] NovM adds ring C (L-noviose) to the hydroxyl group derived from tyrosine with the loss of dTDP. Another methylation is accomplished by NovP and SAM at the 4 position of the L-noviose sugar. [28] This methylation allows NovN to carbamylate the 3 position of the sugar as shown in Fig. 4 completing the biosynthesis of novobiocin.

Figure 4. Completed biosynthesis of novobiocin from ring systems A, B, and C. Mandler NovRevisionsFig4.tif
Figure 4. Completed biosynthesis of novobiocin from ring systems A, B, and C.

Related Research Articles

DNA topoisomerases are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues in DNA arise due to the intertwined nature of its double-helical structure, which, for example, can lead to overwinding of the DNA duplex during DNA replication and transcription. If left unchanged, this torsion would eventually stop the DNA or RNA polymerases involved in these processes from continuing along the DNA helix. A second topological challenge results from the linking or tangling of DNA during replication. Left unresolved, links between replicated DNA will impede cell division. The DNA topoisomerases prevent and correct these types of topological problems. They do this by binding to DNA and cutting the sugar-phosphate backbone of either one or both of the DNA strands. This transient break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNA backbone is resealed. Since the overall chemical composition and connectivity of the DNA do not change, the DNA substrate and product are chemical isomers, differing only in their topology.

DNA gyrase, or simply gyrase, is an enzyme within the class of topoisomerase and is a subclass of Type II topoisomerases that reduces topological strain in an ATP dependent manner while double-stranded DNA is being unwound by elongating RNA-polymerase or by helicase in front of the progressing replication fork. It is the only known enzyme to actively contribute negative supercoiling to DNA, while it also is capable of relaxing positive supercoils. It does so by looping the template to form a crossing, then cutting one of the double helices and passing the other through it before releasing the break, changing the linking number by two in each enzymatic step. This process occurs in bacteria, whose single circular DNA is cut by DNA gyrase and the two ends are then twisted around each other to form supercoils. Gyrase is also found in eukaryotic plastids: it has been found in the apicoplast of the malarial parasite Plasmodium falciparum and in chloroplasts of several plants. Bacterial DNA gyrase is the target of many antibiotics, including nalidixic acid, novobiocin, albicidin, and ciprofloxacin.

<span class="mw-page-title-main">Clavulanic acid</span> Molecule used to overcome antibiotic resistance in bacteria

Clavulanic acid is a β-lactam drug that functions as a mechanism-based β-lactamase inhibitor. While not effective by itself as an antibiotic, when combined with penicillin-group antibiotics, it can overcome antibiotic resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins.

<span class="mw-page-title-main">Fosmidomycin</span> Chemical compound

Fosmidomycin is an antibiotic that was originally isolated from culture broths of bacteria of the genus Streptomyces. It specifically inhibits DXP reductoisomerase, a key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. It is a structural analogue of 2-C-methyl-D-erythrose 4-phosphate. It inhibits the E. coli enzyme with a KI value of 38 nM (4), MTB at 80 nM, and the Francisella enzyme at 99 nM. Several mutations in the E. coli DXP reductoisomerase were found to confer resistance to fosmidomycin.

<span class="mw-page-title-main">Mitomycins</span> Group of antibiotics

The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces caespitosus or Streptomyces lavendulae. They include mitomycin A, mitomycin B, and mitomycin C. When the name mitomycin occurs alone, it usually refers to mitomycin C, its international nonproprietary name. Mitomycin C is used as a medicine for treating various disorders associated with the growth and spread of cells.

<span class="mw-page-title-main">A23187</span> Chemical compound

A23187 is a mobile ion-carrier that forms stable complexes with divalent cations. A23187 is also known as Calcimycin, Calcium Ionophore, Antibiotic A23187 and Calcium Ionophore A23187. It is produced at fermentation of Streptomyceschartreusensis.

<span class="mw-page-title-main">Platensimycin</span> Chemical compound

Platensimycin, a metabolite of Streptomyces platensis, is an antibiotic, which acts by blocking the enzymes β-ketoacyl-(acyl-carrier-protein ) synthase I/II (FabF/B).

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

<span class="mw-page-title-main">Thienamycin</span> Chemical compound

Thienamycin is one of the most potent naturally produced antibiotics known thus far, discovered in Streptomyces cattleya in 1976. Thienamycin has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes. Thienamycin is a zwitterion at pH 7.

<span class="mw-page-title-main">Oleandomycin</span> Chemical compound

Oleandomycin is a macrolide antibiotic. It is synthesized from strains of Streptomyces antibioticus. It is weaker than erythromycin.

<span class="mw-page-title-main">Aminocoumarin</span> Class of antibiotic chemical compounds

Aminocoumarin is a class of antibiotics that act by an inhibition of the DNA gyrase enzyme involved in the cell division in bacteria. They are derived from Streptomyces species, whose best-known representative – Streptomyces coelicolor – was completely sequenced in 2002. The aminocoumarin antibiotics include:

<span class="mw-page-title-main">Desosamine</span> Chemical compound

Desosamine is a 3-(dimethylamino)-3,4,6-trideoxyhexose found in certain macrolide antibiotics such as the commonly prescribed erythromycin, azithromycin, clarithroymcin, methymycin, narbomycin, oleandomycin, picromycin and roxithromycin. As the name suggests, these macrolide antibiotics contain a macrolide or lactone ring and they are attached to the ring Desosamine which is crucial for bactericidal activity. The biological action of the desosamine-based macrolide antibiotics is to inhibit the bacterial ribosomal protein synthesis. These antibiotics which contain Desosamine are widely used to cure bacterial-causing infections in human respiratory system, skin, muscle tissues, and urethra.

<span class="mw-page-title-main">Clorobiocin</span> Chemical compound

Clorobiocin is an aminocoumarin antibacterial that inhibits the enzyme DNA gyrase.

<span class="mw-page-title-main">Indolocarbazole</span> Class of chemical compounds

Indolocarbazoles (ICZs) are a class of compounds that are under current study due to their potential as anti-cancer as well as antimicrobial drugs and the prospective number of derivatives and uses found from the basic backbone alone. First isolated in 1977, a wide range of structures and derivatives have been found or developed throughout the world. Due to the extensive number of structures available, this review will focus on the more important groups here while covering their occurrence, biological activity, biosynthesis, and laboratory synthesis.

<span class="mw-page-title-main">Sparsomycin</span> Chemical compound

Sparsomycin is a compound, initially discovered as a metabolite of the bacterium Streptomyces sparsogenes, which binds to the 50S ribosomal subunit and inhibits protein synthesis through peptidyl transferase inhibition. As it binds to the 50S ribosomal subunit, it induces translocation on the 30S subunit. It is a nucleotide analogue. It was also formerly thought to be a possible anti-tumor agent, but interest in this drug was later discarded after it was discovered that it resulted in retinopathy and as a tool to study protein synthesis; it is not specific for bacterial ribosomes and so not usable as an antibiotic.

<span class="mw-page-title-main">Pristinamycin IIA</span> Chemical compound

Pristinamycin IIA is a macrolide antibiotic. It is a member of the streptogramin A group of antibiotics and one component of pristinamycin. Pristinamycin IIA was first isolated from the Streptomyces virginiae, but has been isolated from other microorganisms and thus has been given a variety of other names such as Virginiamycin M1, Mikamycin A, and Streptogramin A. Pristinamycin IIA structure was determined by chemical and instrumental techniques, including X-ray crystallography. Pristinamycin IIA is of interest from a biosynthetic viewpoint because it contains the unusual dehydroproline and oxazole ring systems. The only experimental evidence bearing on the formation of the oxazole ring is found in work on the biosynthesis of the alkaloid annuloline.

Ribosomally synthesized and post-translationally modified peptides (RiPPs), also known as ribosomal natural products, are a diverse class of natural products of ribosomal origin. Consisting of more than 20 sub-classes, RiPPs are produced by a variety of organisms, including prokaryotes, eukaryotes, and archaea, and they possess a wide range of biological functions.

Streptomyces niveus is a bacterium species from the genus of Streptomyces which has been isolated from soil in the United States. Streptomyces niveus produces the aminocoumarin antibiotic novobiocin and the compounds nivetetracyclate A and nivetetracyclate B.

Streptomyces platensis is a bacterium species from the genus of Streptomyces which has been isolated from soil. Streptomyces platensis produces oxytetracycline, platensimycin, migrastatin, isomigrastatin, platencin, dorrigocin A, dorrigocin B and terramycine.

Streptomyces rishiriensis is a bacterium species from the genus of Streptomyces which has been isolated from soil in Hokkaido in Japan. Streptomyces rishiriensis produces coumermycin A1, notomycin, 2-chloroadenosine, phosphophenylalanarginine and lactonamycin.

References

  1. ↑ Lanoot B, Vancanneyt M, Cleenwerck I, Wang L, Li W, Liu Z, Swings J (May 2002). "The search for synonyms among streptomycetes by using SDS-PAGE of whole-cell proteins. Emendation of the species Streptomyces aurantiacus, Streptomyces cacaoi subsp. cacaoi, Streptomyces caeruleus and Streptomyces violaceus". International Journal of Systematic and Evolutionary Microbiology. 52 (Pt 3): 823–9. doi:10.1099/00207713-52-3-823. PMID   12054245.
  2. 1 2 da Silva Eustáquio A (2004). Biosynthesis of aminocoumarin antibiotics in Streptomyces: Generation of structural analogues by genetic engineering and insights into the regulation of antibiotic production (Ph.D. thesis). Universität Tübingen.
  3. ↑ Hoeksema H, Johnson JL, Hinman JW (December 1955). "Structural studies on streptonivicin, a new antibiotic". Journal of the American Chemical Society. 77 (24): 6710–6711. Bibcode:1955JAChS..77R6710H. doi:10.1021/ja01629a129.
  4. ↑ Smith CG, Dietz A, Sokolski WT, Savage GM (February 1956). "Streptonivicin, a new antibiotic. I. Discovery and biologic studies". Antibiotics & Chemotherapy. 6 (2): 135–142. PMID   24543916.
  5. ↑ Raad I, Darouiche R, Hachem R, Sacilowski M, Bodey GP (November 1995). "Antibiotics and prevention of microbial colonization of catheters". Antimicrobial Agents and Chemotherapy. 39 (11): 2397–400. doi:10.1128/aac.39.11.2397. PMC   162954 . PMID   8585715.
  6. ↑ Raad II, Hachem RY, Abi-Said D, Rolston KV, Whimbey E, Buzaid AC, Legha S (January 1998). "A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2". Cancer. 82 (2): 403–11. doi:10.1002/(SICI)1097-0142(19980115)82:2<412::AID-CNCR22>3.0.CO;2-0. PMID   9445199. S2CID   10940970.
  7. ↑ "Determination That ALBAMYCIN (Novobiocin Sodium) Capsule, 250 Milligrams, Was Withdrawn From Sale for Reasons of Safety or Effectiveness". The Federal Register. 19 January 2011.
  8. ↑ Mintz M (August 1969). "FDA and Panalba: A Conflict of Commercial, Therapeutic Goals?". Science. 165 (3896): 875–881. Bibcode:1969Sci...165..875M. doi:10.1126/science.165.3896.875. PMID   5819616.
  9. ↑ Mintz M. "Upjohn's Shuck and Jive Routine". Mother Jones. Mother Jones and the Foundation for National Progress. Retrieved 16 February 2022.
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  11. 1 2 Maxwell A (August 1993). "The interaction between coumarin drugs and DNA gyrase". Molecular Microbiology. 9 (4): 681–6. doi:10.1111/j.1365-2958.1993.tb01728.x. PMID   8231802. S2CID   43159068.
  12. ↑ Maxwell A (February 1999). "DNA gyrase as a drug target". Biochemical Society Transactions. 27 (2): 48–53. doi:10.1042/bst0270048. PMID   10093705.
  13. ↑ Lewis RJ, Tsai FT, Wigley DB (August 1996). "Molecular mechanisms of drug inhibition of DNA gyrase". BioEssays. 18 (8): 661–71. doi:10.1002/bies.950180810. PMID   8760340. S2CID   9488669.
  14. ↑ Maxwell A, Lawson DM (2003). "The ATP-binding site of type II topoisomerases as a target for antibacterial drugs". Current Topics in Medicinal Chemistry. 3 (3): 283–303. doi:10.2174/1568026033452500. PMID   12570764.
  15. ↑ Yu XM, Shen G, Neckers L, Blake H, Holzbeierlein J, Cronk B, Blagg BS (September 2005). "Hsp90 inhibitors identified from a library of novobiocin analogues". Journal of the American Chemical Society. 127 (37): 12778–9. Bibcode:2005JAChS.12712778Y. doi:10.1021/ja0535864. PMID   16159253.
  16. ↑ Mandler MD, Baidin V, Lee J, Pahil KS, Owens TW, Kahne D (June 2018). "Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport". Journal of the American Chemical Society. 140 (22): 6749–6753. Bibcode:2018JAChS.140.6749M. doi:10.1021/jacs.8b02283. PMC   5990483 . PMID   29746111.
  17. ↑ May JM, Owens TW, Mandler MD, Simpson BW, Lazarus MB, Sherman DJ, Davis RM, Okuda S, Massefski W, Ruiz N, Kahne D (December 2017). "The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport". Journal of the American Chemical Society. 139 (48): 17221–17224. Bibcode:2017JAChS.13917221M. doi:10.1021/jacs.7b07736. PMC   5735422 . PMID   29135241.
  18. ↑ Zhou J, Gelot C, Pantelidou C, Li A, Yücel H, Davis RE, Färkkilä A, Kochupurakkal B, Syed A, Shapiro GI, Tainer JA, Blagg BS, Ceccaldi R, D'Andrea AD (June 2021). "A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors". Nature Cancer. 2 (June 2021): 598–610. doi:10.1038/s43018-021-00203-x. PMC   8224818 . PMID   34179826. S2CID   235659640.
  19. ↑ Tsai FT, Singh OM, Skarzynski T, Wonacott AJ, Weston S, Tucker A, Pauptit RA, Breeze AL, Poyser JP, O'Brien R, Ladbury JE, Wigley DB (May 1997). "The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin". Proteins. 28 (1): 41–52. doi:10.1002/(sici)1097-0134(199705)28:1<41::aid-prot4>3.3.co;2-b. PMID   9144789.
  20. 1 2 Flatman RH, Eustaquio A, Li SM, Heide L, Maxwell A (April 2006). "Structure-activity relationships of aminocoumarin-type gyrase and topoisomerase IV inhibitors obtained by combinatorial biosynthesis". Antimicrobial Agents and Chemotherapy. 50 (4): 1136–42. doi:10.1128/AAC.50.4.1136-1142.2006. PMC   1426943 . PMID   16569821.
  21. ↑ Steffensky M, Mühlenweg A, Wang ZX, Li SM, Heide L (May 2000). "Identification of the novobiocin biosynthetic gene cluster of Streptomyces spheroides NCIB 11891". Antimicrobial Agents and Chemotherapy. 44 (5): 1214–22. doi:10.1128/AAC.44.5.1214-1222.2000. PMC   89847 . PMID   10770754.
  22. ↑ Pojer F, Wemakor E, Kammerer B, Chen H, Walsh CT, Li SM, Heide L (March 2003). "CloQ, a prenyltransferase involved in clorobiocin biosynthesis". Proceedings of the National Academy of Sciences of the United States of America. 100 (5): 2316–21. Bibcode:2003PNAS..100.2316P. doi: 10.1073/pnas.0337708100 . PMC   151338 . PMID   12618544.
  23. ↑ Pojer F, Kahlich R, Kammerer B, Li SM, Heide L (August 2003). "CloR, a bifunctional non-heme iron oxygenase involved in clorobiocin biosynthesis". The Journal of Biological Chemistry. 278 (33): 30661–8. doi: 10.1074/jbc.M303190200 . PMID   12777382.
  24. ↑ Chen H, Walsh CT (April 2001). "Coumarin formation in novobiocin biosynthesis: beta-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI". Chemistry & Biology. 8 (4): 301–12. doi: 10.1016/S1074-5521(01)00009-6 . PMID   11325587.
  25. ↑ Pacholec M, Hillson NJ, Walsh CT (September 2005). "NovJ/NovK catalyze benzylic oxidation of a beta-hydroxyl tyrosyl-S-pantetheinyl enzyme during aminocoumarin ring formation in novobiocin biosynthesis". Biochemistry. 44 (38): 12819–26. CiteSeerX   10.1.1.569.1481 . doi:10.1021/bi051297m. PMID   16171397.
  26. ↑ Thuy TT, Lee HC, Kim CG, Heide L, Sohng JK (April 2005). "Functional characterizations of novWUS involved in novobiocin biosynthesis from Streptomyces spheroides". Archives of Biochemistry and Biophysics. 436 (1): 161–7. doi:10.1016/j.abb.2005.01.012. PMID   15752721.
  27. ↑ Pacholec M, Tao J, Walsh CT (November 2005). "CouO and NovO: C-methyltransferases for tailoring the aminocoumarin scaffold in coumermycin and novobiocin antibiotic biosynthesis". Biochemistry. 44 (45): 14969–76. doi:10.1021/bi051599o. PMID   16274243.
  28. ↑ Freel Meyers CL, Oberthür M, Xu H, Heide L, Kahne D, Walsh CT (January 2004). "Characterization of NovP and NovN: completion of novobiocin biosynthesis by sequential tailoring of the noviosyl ring". Angewandte Chemie. 43 (1): 67–70. doi:10.1002/anie.200352626. PMID   14694473.
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