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Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank').
m In this WikiPedia entry "geldanamycin" is classified as an "anti-tumor anti-biotic". This is ambiguous language with high con­fusion potential. Traditionally, anti-biotics target bacteria specifically. Geldanamycin does not fit this mold: it targets proteins & cell dynamics. Imho, it is better to call it an "anti-tumor agent", because "anti-biotic" will be easily mis­understood by laypeople.
 
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{{chembox
{{Chembox
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| ImageFile = Geldanamycin.svg
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| IUPACName = (4''E'',6''Z'',8''S'',9''S'',10''E'',12''S'',13''R'',14''S'',16''R'')-13-hydroxy<br/>
| IUPACName = (4''E'',6''Z'',8''S'',9''S'',10''E'',12''S'',13''R'',14''S'',16''R'')-13-hydroxy-<wbr/>8,14,19-trimethoxy-4,10,12,16-tetramethyl<wbr/>-3,20,22-trioxo-2-azabicyclo[16.3.1]<wbr/>docosa-1(21),4,6,10,18-pentaen-9-yl carbamate
-8,14,19-trimethoxy-4,10,12,16-tetramethyl<br/>
-3,20,22-trioxo-2-azabicyclo[16.3.1]<br/>
docosa-1(21),4,6,10,18-pentaen-9-yl carbamate
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| StdInChIKey = QTQAWLPCGQOSGP-KSRBKZBZSA-N
| StdInChIKey = QTQAWLPCGQOSGP-KSRBKZBZSA-N
| InChIKey1 = QTQAWLPCGQOSGP-KSRBKZBZSA-N
| InChIKey1 = QTQAWLPCGQOSGP-KSRBKZBZSA-N
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| CASNo = 30562-34-6
| CASNo = 30562-34-6
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| UNII = Z3K3VJ16KU
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| DrugBank = DB02424
| DrugBank = DB02424
| SMILES = NC(=O)O[C@H]1C(/C)=C/[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)C\C2=C(/OC)C(=O)\C=C(\NC(=O)C(\C)=C\C=C/[C@@H]1OC)C2=O
| SMILES = NC(=O)O[C@H]1C(/C)=C/[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)C\C2=C(/OC)C(=O)\C=C(\NC(=O)C(\C)=C\C=C/[C@@H]1OC)C2=O
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| Formula = C<sub>29</sub>H<sub>40</sub>N<sub>2</sub>O<sub>9</sub>
| Formula = C<sub>29</sub>H<sub>40</sub>N<sub>2</sub>O<sub>9</sub>
| MolarMass = 560.64 g/mol
| MolarMass = 560.64 g/mol
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'''Geldanamycin''' is a [[benzoquinone]] [[ansamycin]] [[antibiotic]] that binds to [[Hsp90]] (Heat Shock Protein 90) and inhibits its function. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, [[apoptosis]], [[angiogenesis]] and [[oncogenesis]].
'''Geldanamycin''' is a [[1,4-benzoquinone]] [[ansamycin]] [[Antitumor agent|antitumor antibiotic]] that inhibits the function of [[Hsp90]] (Heat Shock Protein 90) by binding to the unusual ADP/ATP-binding pocket of the protein.<ref>{{Cite journal
| last1 = Schulte | first1 = T. W.
| last2 = Akinaga | first2 = S.
| last3 = Soga | first3 = S.
| last4 = Sullivan | first4 = W.
| last5 = Stensgard | first5 = B.
| last6 = Toft | first6 = D.
| last7 = Neckers | first7 = L. M.
| title = Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin
| journal = Cell Stress & Chaperones
| volume = 3
| issue = 2
| pages = 100–108
| year = 1998
| doi = 10.1379/1466-1268(1998)003<0100:ARBTTN>2.3.CO;2
| doi-broken-date = 2024-04-26
| pmid = 9672245
| pmc = 312953
}}</ref> HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, [[apoptosis]], [[angiogenesis]] and [[oncogenesis]].<ref>{{cite book |last1=Wayne |first1=N. |last2=Mishra |first2=P. |last3=Bolon |first3=D.N. |title=Molecular Chaperones |chapter=Hsp90 and Client Protein Maturation |series=Methods Mol Biol. |date=2011 |volume=787 |pages=33–44 |doi=10.1007/978-1-61779-295-3_3 |pmid=21898225 |pmc=5078872 |isbn=978-1-61779-294-6 }}</ref>


[[File:1yetgdm.png|thumb|Hsp90-geldanamycin complex. PDB {{PDBe|1yet}}<ref>{{Cite journal
Geldanamycin induces the degradation of proteins that are mutated in [[tumor]] cells such as [[v-Src]], [[Bcr-Abl]] and [[p53]] preferentially over their normal cellular counterparts. This effect is mediated via HSP90. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate (namely, [[hepatotoxicity]]) that have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position:
| last1 = Stebbins | first1 = C. E.
| last2 = Russo | first2 = A. A.
| last3 = Schneider | first3 = C.
| last4 = Rosen | first4 = N.
| last5 = Hartl | first5 = F. U.
| last6 = Pavletich | first6 = N. P.
| title = Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent
| journal = Cell
| volume = 89
| issue = 2
| pages = 239–250
| year = 1997
| pmid = 9108479 | doi=10.1016/S0092-8674(00)80203-2
| s2cid = 5253110
| doi-access = free
}}</ref>]]Geldanamycin induces the degradation of proteins that are mutated or overexpressed in [[tumor]] cells such as [[v-Src]], [[Bcr-Abl]], [[p53]], and [[ERBB2]]. This effect is mediated via HSP90. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate such as [[hepatotoxicity]], further, Jilani ''et al.''. reported that geldanamycin induces the [[apoptosis]] of [[erythrocytes]] under physiological concentrations.<ref>{{Cite journal | last1 = Jilani| first1 = Kashif| last2 = Qadri| first2 = Syed M.| last3 = Lang| first3 = Florian| year = 2013 | title = Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane | journal = Cell Physiol Biochem | volume = 32 | issue = 6| pages = 1600–1609 | doi = 10.1159/000356596 | pmid = 24335345| doi-access = free}}</ref> These side effects have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position:


* [[17-AAG]]
* [[17-AAG]]
* [[17-DMAG]]
* [[17-DMAG]]


==Biosynthesis==
== Biosynthesis ==


Geldanamycin was originally discovered in the organism ''[[Streptomyces]] hygroscopicus''.<ref>He, W.; Wu, L; Gao, Q.; Du, Y.; Wang, Y. Identification of AHBA Biosynthetic Genes Related to Geldanamycin
Geldanamycin was originally discovered in the organism ''[[Streptomyces hygroscopicus]]''.<ref>{{Cite journal
| last1 = He | first1 = W.
Biosynthesis in Streptomyces hygroscopicus 17997. Current Microbiology 2006. 52, 197-203.</ref> It is a macrocyclic polyketide that is synthesized by a Type I [[polyketide synthase]]. The genes gelA, gelB, and gelC encode for the polyketide synthase. The PKS is first loaded with 3-amino-5-hydroxybenzoic acid (AHBA). It then utilizes [[malonyl-CoA]], [[methylmalonyl-CoA]], and methoxymalonyl-CoA to synthesize the precursor molecule Progeldanamycin. <ref>Kim, W.; Lee, D.; Hong, S. S.; Na, Z.; Shin, J. C.; Roh, S. H.; Wu, C.; Choi, O.; Lee, K.; Shen, Y.; Paik, S.; Lee, J. J.; Hong, Y. Rational Biosynthetic Engineering for Optimization of
| last2 = Wu | first2 = L.
Geldanamycin Analogues. ChemBioChem 2009. 10, 1243-1251.</ref> This precursor is subjected to several enzymatic and non-enzymatic tailoring steps to produce the active molecule Geldanamycin, which include hydroxylation, o-methylation, carbamoylation, and oxidation.<ref>Lee, D.; Lee, K; Cai, X. F.; Dat, N. T.; Boovanahalli, S. K.; Lee, M.; Shin, J. C.; Kim, W.; Jeong, J. K.; Lee, J. S.; Lee, C.; Lee, J.; Hong, Y.; Lee, J. J. Biosynthesis of the Heat-Shock
| last3 = Gao | first3 = Q.
Protein 90 Inhibitor Geldanamycin: New Insight into the Formation of the Benzoquinone Moiety. ChemBioChem 2006. 7, 246-248.</ref>
| last4 = Du | first4 = Y.
| last5 = Wang | first5 = Y.
| title = Identification of AHBA Biosynthetic Genes Related to Geldanamycin Biosynthesis in Streptomyces hygroscopicus 17997
| doi = 10.1007/s00284-005-0203-y
| journal = Current Microbiology
| volume = 52
| issue = 3
| pages = 197–203
| year = 2006
| pmid = 16502293
| s2cid = 22291736
}}</ref> It is a macrocyclic polyketide that is synthesized by a Type I [[polyketide synthase]]. The genes gelA, gelB, and gelC encode for the polyketide synthase. The PKS is first loaded with 3-amino-5-hydroxybenzoic acid (AHBA). It then utilizes [[malonyl-CoA]], [[methylmalonyl-CoA]], and methoxymalonyl-CoA to synthesize the precursor molecule Progeldanamycin.<ref>{{Cite journal
| last1 = Kim | first1 = W.
| last2 = Lee | first2 = D.
| last3 = Hong | first3 = S. S.
| last4 = Na | first4 = Z.
| last5 = Shin | first5 = J. C.
| last6 = Roh | first6 = S. H.
| last7 = Wu | first7 = C. Z.
| last8 = Choi | first8 = O.
| last9 = Lee | first9 = K.
| last10 = Shen | first10 = Y. M.
| last11 = Paik | first11 = S. G.
| last12 = Lee | first12 = J. J.
| last13 = Hong | first13 = Y. S.
| title = Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues
| doi = 10.1002/cbic.200800763
| journal = ChemBioChem
| volume = 10
| issue = 7
| pages = 1243–1251
| year = 2009
| pmid = 19308924
| s2cid = 3273370
}}</ref> This precursor is subjected to several enzymatic and non-enzymatic tailoring steps to produce the active molecule Geldanamycin, which include hydroxylation, o-methylation, carbamoylation, and oxidation.<ref>{{Cite journal
| last1 = Lee | first1 = D.
| last2 = Lee | first2 = K.
| last3 = Cai | first3 = X. F.
| last4 = Dat | first4 = N. T.
| last5 = Boovanahalli | first5 = S. K.
| last6 = Lee | first6 = M.
| last7 = Shin | first7 = J. C.
| last8 = Kim | first8 = W.
| last9 = Jeong | first9 = J. K.
| last10 = Lee | first10 = J. S.
| last11 = Lee | first11 = C. H.
| last12 = Lee | first12 = J. H.
| last13 = Hong | first13 = Y. S.
| last14 = Lee | first14 = J. J.
| title = Biosynthesis of the Heat-Shock Protein 90 Inhibitor Geldanamycin: New Insight into the Formation of the Benzoquinone Moiety
| doi = 10.1002/cbic.200500441
| journal = ChemBioChem
| volume = 7
| issue = 2
| pages = 246–248
| year = 2006
| pmid = 16381049
| s2cid = 42998903
}}</ref>


== Notes ==


Figure 1. The PKS domain arrangement and tailoring steps required to synthesize Geldanamycin.

==Notes==
{{reflist}}
{{reflist}}


== References ==
* {{Cite journal
| last1 = Bedin | first1 = M.
| last2 = Gaben | first2 = A. M.
| last3 = Saucier | first3 = C. C.
| last4 = Mester | first4 = J.
| title = Geldanamycin, an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest
| doi = 10.1002/ijc.20010
| journal = International Journal of Cancer
| volume = 109
| issue = 5
| pages = 643–652
| year = 2004
| pmid = 14999769
| s2cid = 39451213
| doi-access = free
}}


== External links ==
==References==
* '''Bedin M, Gaben AM, Saucier C, Mester J.''' '''Int J Cancer. 2004 May 1;109(5):643-52'''. Geldanamycin, an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest.

==External links==
*[http://geldanamycin.info/index.htm A comprehensive review about Geldanamycin, 17AAG and 17DMAG]
*[http://geldanamycin.info/index.htm A comprehensive review about Geldanamycin, 17AAG and 17DMAG]
*[http://www.fermentek.co.il/geldanamycin.htm Geldanamycin from ] [[Fermentek]]
*[http://www.fermentek.co.il/geldanamycin.htm Geldanamycin from ] [[Fermentek]]
*[https://web.archive.org/web/20151122093256/http://pharmacy.mc.uky.edu/cpri/snpa.php Geldanamycin from ] [[Center for Pharmaceutical Research and Innovation]]
* [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=GDM Geldanamycin bound to proteins] in the [[Protein Data Bank|PDB]]


[[Category:Antibiotics]]
[[Category:1,4-Benzoquinones]]
[[Category:Quinones]]
[[Category:Carbamates]]
[[Category:Carbamates]]
[[Category:Lactams]]
[[Category:Lactams]]
[[Category:Phenol ethers]]
[[Category:Phenol ethers]]
[[Category:Ethers]]
[[Category:Ethers]]
[[Category:Alcohols]]
[[Category:Secondary alcohols]]
[[Category:Ansamycins]]

[[de:Geldanamycin]]
[[pl:Geldanamycyna]]
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