Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Novobiocin: Difference between pages

{{Short description|Chemical compound}}

{{cs1 config|name-list-style=vanc}}

{{distinguish|text=the siderophore antibiotic [[albomycin]]}}

| Watchedfields = changed

| verifiedrevid = 462263512

| IUPAC_name = 4-Hydroxy-3-[4-hydroxy-3-(3-methylbut-2-enyl)benzamido]-8-methylcoumarin-7-yl 3-''O''-carbamoyl-5,5-di-''C''-methyl-αあるふぁ-<small>L</small>-lyxofuranoside

| image = Novobiocin2DCSD.svg

| width = 260px

| image2 = Novobiocin molecule spacefill.png

| width2 = 240

| alt2 = Space-filling model of the novobiocin molecule

| tradename =

| pregnancy_category =

| legal_status =

| ATCvet = yes

| ATC_prefix = J01

| ATC_suffix = XX95

| KEGG_Ref = {{keggcite|correct|kegg}}

| C=31 | H=36 | N=2 | O=11

| smiles = 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

| melting_point = 152

| melting_high = 156

| melting_notes = (dec.)

'''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''<ref>{{cite journal | vauthors = Lanoot B, Vancanneyt M, Cleenwerck I, Wang L, Li W, Liu Z, Swings J | title = 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 | journal = International Journal of Systematic and Evolutionary Microbiology | volume = 52 | issue = Pt 3 | pages = 823–9 | date = May 2002 | pmid = 12054245 | doi = 10.1099/00207713-52-3-823 }}</ref> a member of the class [[Actinomycetia]]. Other aminocoumarin antibiotics include clorobiocin and coumermycin A1.<ref name=E>{{cite thesis | vauthors = da Silva Eustáquio A | degree = Ph.D. | publisher = Universität Tübingen | date = 2004 | title = Biosynthesis of aminocoumarin antibiotics in Streptomyces: Generation of structural analogues by genetic engineering and insights into the regulation of antibiotic production | url = https://ub01.uni-tuebingen.de/xmlui/handle/10900/48693 }}

</ref> Novobiocin was first reported in the mid-1950s (then called '''streptonivicin''').<ref>{{cite journal | vauthors = Hoeksema H, Johnson JL, Hinman JW | date = December 1955 | title = Structural studies on streptonivicin, a new antibiotic | journal = Journal of the American Chemical Society | volume = 77 | issue = 24| pages = 6710–6711 | doi=10.1021/ja01629a129}}</ref><ref>{{cite journal | vauthors = Smith CG, Dietz A, Sokolski WT, Savage GM | title = Streptonivicin, a new antibiotic. I. Discovery and biologic studies | journal = Antibiotics & Chemotherapy | volume = 6 | issue = 2 | pages = 135–142 | date = February 1956 | pmid = 24543916 }}</ref>

==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.{{cn|date=February 2023}}

Novobiocin was licensed for clinical use under the tradename Albamycin ([[Upjohn]]) in the 1960s. Its [[efficacy#Pharmacology|efficacy]] has been demonstrated in

[[Clinical trial#Pre clinical studies|preclinical]] and [[Clinical trial|clinical]] trials.<ref>{{cite journal | vauthors = Raad I, Darouiche R, Hachem R, Sacilowski M, Bodey GP | title = Antibiotics and prevention of microbial colonization of catheters | journal = Antimicrobial Agents and Chemotherapy | volume = 39 | issue = 11 | pages = 2397–400 | date = November 1995 | pmid = 8585715 | pmc = 162954 | doi = 10.1128/aac.39.11.2397 }}</ref><ref>{{cite journal | vauthors = Raad II, Hachem RY, Abi-Said D, Rolston KV, Whimbey E, Buzaid AC, Legha S | title = A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2 | journal = Cancer | volume = 82 | issue = 2 | pages = 403–11 | date = January 1998 | pmid = 9445199 | doi = 10.1002/(SICI)1097-0142(19980115)82:2<412::AID-CNCR22>3.0.CO;2-0 | s2cid = 10940970 }}</ref> The oral form of the drug has since been withdrawn from the market due to lack of efficacy.<ref>{{cite web | title = Determination That ALBAMYCIN (Novobiocin Sodium) Capsule, 250 Milligrams, Was Withdrawn From Sale for Reasons of Safety or Effectiveness | date = 19 January 2011 | work = The Federal Register | url = https://www.federalregister.gov/articles/2011/01/19/2011-1000/determination-that-albamycin-novobiocin-sodium-capsule-250-milligrams-was-withdrawn-from-sale-for }}</ref> 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.<ref>{{cite journal | vauthors = Mintz M | title = FDA and Panalba: A Conflict of Commercial, Therapeutic Goals? | language = EN | journal = Science | volume = 165 | issue = 3896 | pages = 875–881 | date = August 1969 | doi = 10.1126/science.165.3896.875 | pmid = 5819616 | bibcode = 1969Sci...165..875M }}</ref><ref>{{cite web | vauthors = Mintz M |title=Upjohn's Shuck and Jive Routine |url=https://www.motherjones.com/politics/1979/11/upjohns-shuck-and-jive-routine/ |website=Mother Jones |publisher=Mother Jones and the Foundation for National Progress |access-date=16 February 2022}}</ref> Novobiocin is an effective [[Staphylococcus|antistaphylococcal]] agent used in the treatment of [[Methicillin-resistant Staphylococcus aureus|MRSA]].<ref>{{cite journal | vauthors = Walsh TJ, Standiford HC, Reboli AC, John JF, Mulligan ME, Ribner BS, Montgomerie JZ, Goetz MB, Mayhall CG, Rimland D | title = Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome | journal = Antimicrobial Agents and Chemotherapy | volume = 37 | issue = 6 | pages = 1334–42 | date = June 1993 | pmid = 8328783 | pmc = 187962 | doi = 10.1128/aac.37.6.1334 }}</ref>

== Mechanism of action ==

The molecular basis of action of '''novobiocin''', and other related drugs [[clorobiocin]] and [[coumermycin A1]] has been examined.<ref name=E/><ref name=M>{{cite journal | vauthors = Maxwell A | title = The interaction between coumarin drugs and DNA gyrase | journal = Molecular Microbiology | volume = 9 | issue = 4 | pages = 681–6 | date = August 1993 | pmid = 8231802 | doi = 10.1111/j.1365-2958.1993.tb01728.x | s2cid = 43159068 }}</ref><ref>{{cite journal | vauthors = Maxwell A | title = DNA gyrase as a drug target | journal = Biochemical Society Transactions | volume = 27 | issue = 2 | pages = 48–53 | date = February 1999 | pmid = 10093705 | doi = 10.1042/bst0270048 }}</ref><ref>{{cite journal | vauthors = Lewis RJ, Tsai FT, Wigley DB | title = Molecular mechanisms of drug inhibition of DNA gyrase | journal = BioEssays | volume = 18 | issue = 8 | pages = 661–71 | date = August 1996 | pmid = 8760340 | doi = 10.1002/bies.950180810 | s2cid = 9488669 }}</ref><ref>{{cite journal | vauthors = Maxwell A, Lawson DM | title = The ATP-binding site of type II topoisomerases as a target for antibacterial drugs | journal = Current Topics in Medicinal Chemistry | volume = 3 | issue = 3 | pages = 283–303 | year = 2003 | pmid = 12570764 | doi = 10.2174/1568026033452500 }}</ref> Aminocoumarins are very [[potency (pharmacology)|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]] [[antibiotic]]s act as competitive inhibitors of the [[ATPase]] reaction catalysed by GyrB. The potency of novobiocin is considerably higher than that of the [[fluoroquinolone]]s 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.{{cn|date=February 2023}}

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.<ref>{{cite journal | vauthors = Yu XM, Shen G, Neckers L, Blake H, Holzbeierlein J, Cronk B, Blagg BS | title = Hsp90 inhibitors identified from a library of novobiocin analogues | journal = Journal of the American Chemical Society | volume = 127 | issue = 37 | pages = 12778–9 | date = September 2005 | pmid = 16159253 | doi = 10.1021/ja0535864 }}</ref> Novobiocin has also been shown to bind and activate the Gram-negative lipopolysaccharide transporter LptBFGC.<ref>{{cite journal | vauthors = Mandler MD, Baidin V, Lee J, Pahil KS, Owens TW, Kahne D | title = Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport | journal = Journal of the American Chemical Society | volume = 140 | issue = 22 | pages = 6749–6753 | date = June 2018 | pmid = 29746111 | pmc = 5990483 | doi = 10.1021/jacs.8b02283 }}</ref><ref>{{cite journal | vauthors = May JM, Owens TW, Mandler MD, Simpson BW, Lazarus MB, Sherman DJ, Davis RM, Okuda S, Massefski W, Ruiz N, Kahne D | title = The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport | language = EN | journal = Journal of the American Chemical Society | volume = 139 | issue = 48 | pages = 17221–17224 | date = December 2017 | pmid = 29135241 | pmc = 5735422 | doi = 10.1021/jacs.7b07736 }}</ref>

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. <ref>{{cite journal | vauthors =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 | title = A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors | language = EN | journal = Nature Cancer | volume = 2 | issue = June 2021 | pages = 598–610 | date = June 2021 | pmid=34179826| doi = 10.1038/s43018-021-00203-x|pmc=8224818 | s2cid = 235659640 }}</ref>

== Structure ==

Novobiocin is an aminocoumarin. Novobiocin may be divided up into three entities; a benzoic acid derivative, a coumarin residue, and the sugar novobiose.<ref name=M/> [[X-ray crystallography|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.<ref>{{cite journal | vauthors = 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 | title = 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 | journal = Proteins | volume = 28 | issue = 1 | pages = 41–52 | date = May 1997 | pmid = 9144789 | doi = 10.1002/(sici)1097-0134(199705)28:1<41::aid-prot4>3.3.co;2-b }}</ref> The overlap of the coumarin and ATP-binding sites is consistent with aminocoumarins being competitive inhibitors of the ATPase activity.<ref name=Flatman2006>{{cite journal | vauthors = Flatman RH, Eustaquio A, Li SM, Heide L, Maxwell A | title = Structure-activity relationships of aminocoumarin-type gyrase and topoisomerase IV inhibitors obtained by combinatorial biosynthesis | journal = Antimicrobial Agents and Chemotherapy | volume = 50 | issue = 4 | pages = 1136–42 | date = April 2006 | pmid = 16569821 | pmc = 1426943 | doi = 10.1128/AAC.50.4.1136-1142.2006 }}</ref>

===Structure–activity relationship===

In [[Structure-activity relationship|structure activity relationship]] experiments it was found that removal of the [[carbamoyl|carbamoyl group]] located on the novobiose sugar lead to a dramatic decrease in inhibitory activity of novobiocin.<ref name=Flatman2006/>

==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 <small>L</small>-tyrosine. The final component of novobiocin is the sugar derivative <small>L</small>-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.<ref name="pmid10770754">{{cite journal | vauthors = Steffensky M, Mühlenweg A, Wang ZX, Li SM, Heide L | title = Identification of the novobiocin biosynthetic gene cluster of Streptomyces spheroides NCIB 11891 | journal = Antimicrobial Agents and Chemotherapy | volume = 44 | issue = 5 | pages = 1214–22 | date = May 2000 | pmid = 10770754 | pmc = 89847 | doi = 10.1128/AAC.44.5.1214-1222.2000 }}</ref> They identified 23 putative open reading frames (ORFs) and more than 11 other ORFs that may play a role in novobiocin biosynthesis.{{cn|date=February 2023}}

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.<ref name="pmid12618544">{{cite journal | vauthors = Pojer F, Wemakor E, Kammerer B, Chen H, Walsh CT, Li SM, Heide L | title = CloQ, a prenyltransferase involved in clorobiocin biosynthesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 5 | pages = 2316–21 | date = March 2003 | pmid = 12618544 | pmc = 151338 | doi = 10.1073/pnas.0337708100 | bibcode = 2003PNAS..100.2316P | doi-access = free }}</ref> 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.<ref name="pmid12777382">{{cite journal | vauthors = Pojer F, Kahlich R, Kammerer B, Li SM, Heide L | title = CloR, a bifunctional non-heme iron oxygenase involved in clorobiocin biosynthesis | journal = The Journal of Biological Chemistry | volume = 278 | issue = 33 | pages = 30661–8 | date = August 2003 | pmid = 12777382 | doi = 10.1074/jbc.M303190200 | doi-access = free }}</ref> 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.

[[File:Mandler NovoRevisions.tif|center|400x400px|'''Figure 1.''' Biosynthetic scheme of benzamide portion of novobiocin (4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoic acid)|thumb]]

The biosynthesis of ring B (see '''Fig. 2''') begins with the natural amino acid [[Tyrosine|<small>L</small>-tyrosine]]. This is then adenylated and thioesterified onto the peptidyl carrier protein (PCP) of NovH by [[Adenosine triphosphate|ATP]] and NovH itself.<ref name="pmid11325587">{{cite journal | vauthors = Chen H, Walsh CT | title = Coumarin formation in novobiocin biosynthesis: beta-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI | journal = Chemistry & Biology | volume = 8 | issue = 4 | pages = 301–12 | date = April 2001 | pmid = 11325587 | doi = 10.1016/S1074-5521(01)00009-6 | doi-access = free }}</ref> NovI then further modifies this PCP bound molecule by oxidizing the βべーた-position using [[NADPH]] and molecular oxygen. NovJ and NovK form a heterodimer of J2K2 which is the active form of this benzylic oxygenase.<ref name="pmid16171397">{{cite journal | vauthors = Pacholec M, Hillson NJ, Walsh CT | title = NovJ/NovK catalyze benzylic oxidation of a beta-hydroxyl tyrosyl-S-pantetheinyl enzyme during aminocoumarin ring formation in novobiocin biosynthesis | journal = Biochemistry | volume = 44 | issue = 38 | pages = 12819–26 | date = September 2005 | pmid = 16171397 | doi = 10.1021/bi051297m | citeseerx = 10.1.1.569.1481 }}</ref> This process uses NADP⁺ as a hydride acceptor in the oxidation of the βべーた-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.

[[File:Novobiocin Ring B Synthesis.png|thumb|700px|center|'''Figure 2.''' Biosynthesis of 3-amino-4,7-dihydroxy-2H-chromen-2-one component of novobiocin (ring '''B''')]]

The biosynthesis of <small>L</small>-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.<ref name="pmid15752721">{{cite journal | vauthors = Thuy TT, Lee HC, Kim CG, Heide L, Sohng JK | title = Functional characterizations of novWUS involved in novobiocin biosynthesis from Streptomyces spheroides | journal = Archives of Biochemistry and Biophysics | volume = 436 | issue = 1 | pages = 161–7 | date = April 2005 | pmid = 15752721 | doi = 10.1016/j.abb.2005.01.012 }}</ref> 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]].

[[File:L-Noviose Biosynthesis.png|thumb|700px|center|'''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 [[Adenosine triphosphate|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.<ref name="pmid16274243">{{cite journal | vauthors = Pacholec M, Tao J, Walsh CT | title = CouO and NovO: C-methyltransferases for tailoring the aminocoumarin scaffold in coumermycin and novobiocin antibiotic biosynthesis | journal = Biochemistry | volume = 44 | issue = 45 | pages = 14969–76 | date = November 2005 | pmid = 16274243 | doi = 10.1021/bi051599o }}</ref> NovM adds ring C (<small>L</small>-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 <small>L</small>-noviose sugar.<ref name="pmid14694473">{{cite journal | vauthors = Freel Meyers CL, Oberthür M, Xu H, Heide L, Kahne D, Walsh CT | title = Characterization of NovP and NovN: completion of novobiocin biosynthesis by sequential tailoring of the noviosyl ring | journal = Angewandte Chemie | volume = 43 | issue = 1 | pages = 67–70 | date = January 2004 | pmid = 14694473 | doi = 10.1002/anie.200352626 }}</ref> This methylation allows NovN to carbamylate the 3 position of the sugar as shown in '''Fig. 4''' completing the biosynthesis of novobiocin.

[[File:Mandler NovRevisionsFig4.tif|center|thumb|600x600px|'''Figure 4.''' Completed biosynthesis of novobiocin from ring systems '''A''', '''B''', and '''C'''.

]]

== References ==

{{reflist|colwidth=30em}}

== External links ==

* [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=NOV Novobiocin bound to proteins] in the [[Protein Data Bank|PDB]]

{{Nucleic acid inhibitors}}

{{Clinical microbiology techniques}}

[[Category:Antibiotics]]

[[Category:Coumarin drugs]]

[[Category:Benzamides]]

[[Category:Carbamates]]

[[Category:Topoisomerase inhibitors]]