Geldanamycin: Difference between revisions
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Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank'). |
Esmircalda (talk | contribs) 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 |
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| verifiedrevid = 436772839 |
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| ImageFile = Geldanamycin.svg |
| ImageFile = Geldanamycin.svg |
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| ImageSize = |
| ImageSize = |
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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< |
| 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 |
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-8,14,19-trimethoxy-4,10,12,16-tetramethyl<br/> |
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-3,20,22-trioxo-2-azabicyclo[16.3.1]<br/> |
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docosa-1(21),4,6,10,18-pentaen-9-yl carbamate |
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| OtherNames = |
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|Section1={{Chembox Identifiers |
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| Abbreviations = |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| StdInChIKey = QTQAWLPCGQOSGP-KSRBKZBZSA-N |
| StdInChIKey = QTQAWLPCGQOSGP-KSRBKZBZSA-N |
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| InChIKey1 = QTQAWLPCGQOSGP-KSRBKZBZSA-N |
| InChIKey1 = QTQAWLPCGQOSGP-KSRBKZBZSA-N |
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| CASNo_Ref = {{cascite|correct|??}} |
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| CASNo = 30562-34-6 |
| CASNo = 30562-34-6 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = Z3K3VJ16KU |
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| EINECS = |
| EINECS = |
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| PubChem = |
| PubChem = 5288382 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB02424 |
| DrugBank = DB02424 |
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| 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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| InChI = |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 5292 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
| KEGG_Ref = {{keggcite|correct|kegg}} |
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}} |
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|Section2={{Chembox Properties |
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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> |
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| MolarMass = 560.64 g/mol |
| MolarMass = 560.64 g/mol |
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|Section4={{Chembox Thermochemistry |
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|Section5={{Chembox Pharmacology |
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| Section6 = {{Chembox Explosive |
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|Section7={{Chembox Hazards |
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'''Geldanamycin''' is a [[benzoquinone]] [[ansamycin]] [[antibiotic]] that |
'''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 |
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| last1 = Schulte | first1 = T. W. |
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| last2 = Akinaga | first2 = S. |
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| last3 = Soga | first3 = S. |
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| last4 = Sullivan | first4 = W. |
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| last5 = Stensgard | first5 = B. |
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| last6 = Toft | first6 = D. |
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| last7 = Neckers | first7 = L. M. |
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| title = Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin |
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| journal = Cell Stress & Chaperones |
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| volume = 3 |
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| issue = 2 |
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| pages = 100–108 |
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| year = 1998 |
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| doi = 10.1379/1466-1268(1998)003<0100:ARBTTN>2.3.CO;2 |
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| doi-broken-date = 2024-04-26 |
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| pmid = 9672245 |
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| pmc = 312953 |
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}}</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> |
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[[File:1yetgdm.png|thumb|Hsp90-geldanamycin complex. PDB {{PDBe|1yet}}<ref>{{Cite journal |
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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: |
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| last1 = Stebbins | first1 = C. E. |
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| last2 = Russo | first2 = A. A. |
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| last3 = Schneider | first3 = C. |
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| last4 = Rosen | first4 = N. |
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| last5 = Hartl | first5 = F. U. |
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| last6 = Pavletich | first6 = N. P. |
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| title = Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent |
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| journal = Cell |
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| volume = 89 |
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| issue = 2 |
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| pages = 239–250 |
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| year = 1997 |
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| pmid = 9108479 | doi=10.1016/S0092-8674(00)80203-2 |
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| s2cid = 5253110 |
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| doi-access = free |
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}}</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: |
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* [[17-AAG]] |
* [[17-AAG]] |
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* [[17-DMAG]] |
* [[17-DMAG]] |
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==Biosynthesis== |
== Biosynthesis == |
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Geldanamycin was originally discovered in the organism ''[[Streptomyces]] |
Geldanamycin was originally discovered in the organism ''[[Streptomyces hygroscopicus]]''.<ref>{{Cite journal |
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| last1 = He | first1 = W. |
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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 |
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| last2 = Wu | first2 = L. |
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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 |
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| last3 = Gao | first3 = Q. |
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Protein 90 Inhibitor Geldanamycin: New Insight into the Formation of the Benzoquinone Moiety. ChemBioChem 2006. 7, 246-248.</ref> |
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| last4 = Du | first4 = Y. |
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| last5 = Wang | first5 = Y. |
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| title = Identification of AHBA Biosynthetic Genes Related to Geldanamycin Biosynthesis in Streptomyces hygroscopicus 17997 |
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| doi = 10.1007/s00284-005-0203-y |
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| journal = Current Microbiology |
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| volume = 52 |
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| issue = 3 |
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| pages = 197–203 |
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| year = 2006 |
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| pmid = 16502293 |
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| s2cid = 22291736 |
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}}</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 |
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| last1 = Kim | first1 = W. |
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| last2 = Lee | first2 = D. |
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| last3 = Hong | first3 = S. S. |
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| last4 = Na | first4 = Z. |
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| last5 = Shin | first5 = J. C. |
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| last6 = Roh | first6 = S. H. |
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| last7 = Wu | first7 = C. Z. |
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| last8 = Choi | first8 = O. |
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| last9 = Lee | first9 = K. |
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| last10 = Shen | first10 = Y. M. |
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| last11 = Paik | first11 = S. G. |
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| last12 = Lee | first12 = J. J. |
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| last13 = Hong | first13 = Y. S. |
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| title = Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues |
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| doi = 10.1002/cbic.200800763 |
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| journal = ChemBioChem |
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| volume = 10 |
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| issue = 7 |
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| pages = 1243–1251 |
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| year = 2009 |
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| pmid = 19308924 |
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| s2cid = 3273370 |
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}}</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 |
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| last1 = Lee | first1 = D. |
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| last2 = Lee | first2 = K. |
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| last3 = Cai | first3 = X. F. |
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| last4 = Dat | first4 = N. T. |
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| last5 = Boovanahalli | first5 = S. K. |
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| last6 = Lee | first6 = M. |
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| last7 = Shin | first7 = J. C. |
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| last8 = Kim | first8 = W. |
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| last9 = Jeong | first9 = J. K. |
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| last10 = Lee | first10 = J. S. |
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| last11 = Lee | first11 = C. H. |
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| last12 = Lee | first12 = J. H. |
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| last13 = Hong | first13 = Y. S. |
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| last14 = Lee | first14 = J. J. |
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| title = Biosynthesis of the Heat-Shock Protein 90 Inhibitor Geldanamycin: New Insight into the Formation of the Benzoquinone Moiety |
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| doi = 10.1002/cbic.200500441 |
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| journal = ChemBioChem |
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| volume = 7 |
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| issue = 2 |
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| pages = 246–248 |
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| year = 2006 |
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| pmid = 16381049 |
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| s2cid = 42998903 |
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}}</ref> |
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== Notes == |
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Figure 1. The PKS domain arrangement and tailoring steps required to synthesize Geldanamycin. |
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==Notes== |
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{{reflist}} |
{{reflist}} |
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== References == |
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* {{Cite journal |
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| last1 = Bedin | first1 = M. |
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| last2 = Gaben | first2 = A. M. |
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| last3 = Saucier | first3 = C. C. |
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| last4 = Mester | first4 = J. |
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| title = Geldanamycin, an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest |
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| doi = 10.1002/ijc.20010 |
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| journal = International Journal of Cancer |
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| volume = 109 |
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| issue = 5 |
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| pages = 643–652 |
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| year = 2004 |
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| pmid = 14999769 |
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| s2cid = 39451213 |
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| doi-access = free |
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}} |
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== External links == |
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==References== |
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* '''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. |
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==External links== |
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*[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] |
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*[http://www.fermentek.co.il/geldanamycin.htm Geldanamycin from ] [[Fermentek]] |
*[http://www.fermentek.co.il/geldanamycin.htm Geldanamycin from ] [[Fermentek]] |
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*[https://web.archive.org/web/20151122093256/http://pharmacy.mc.uky.edu/cpri/snpa.php Geldanamycin from ] [[Center for Pharmaceutical Research and Innovation]] |
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* [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=GDM Geldanamycin bound to proteins] in the [[Protein Data Bank|PDB]] |
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[[Category: |
[[Category:1,4-Benzoquinones]] |
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[[Category:Quinones]] |
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[[Category:Carbamates]] |
[[Category:Carbamates]] |
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[[Category:Lactams]] |
[[Category:Lactams]] |
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[[Category:Phenol ethers]] |
[[Category:Phenol ethers]] |
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[[Category:Ethers]] |
[[Category:Ethers]] |
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[[Category: |
[[Category:Secondary alcohols]] |
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[[Category:Ansamycins]] |
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[[de:Geldanamycin]] |
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[[pl:Geldanamycyna]] |