Geldanamycin

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Geldanamycin
Geldanamycin.svg
Names
IUPAC name
(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
PubChem CID
UNII
  • InChI=1S/C29H40N2O9/c1-15-11-19-25(34)20(14-21(32)27(19)39-7)31-28(35)16(2)9-8-10-22(37-5)26(40-29(30)36)18(4)13-17(3)24(33)23(12-15)38-6/h8-10,13-15,17,22-24,26,33H,11-12H2,1-7H3,(H2,30,36)(H,31,35)/b10-8-,16-9+,18-13+/t15-,17+,22+,23+,24-,26+/m1/s1 Yes check.svgY
    Key: QTQAWLPCGQOSGP-KSRBKZBZSA-N Yes check.svgY
  • InChI=1S/C29H40N2O9/c1-15-11-19-25(34)20(14-21(32)27(19)39-7)31-28(35)16(2)9-8-10-22(37-5)26(40-29(30)36)18(4)13-17(3)24(33)23(12-15)38-6/h8-10,13-15,17,22-24,26,33H,11-12H2,1-7H3,(H2,30,36)(H,31,35)/b10-8-,16-9+,18-13+/t15-,17+,22+,23+,24-,26+/m1/s1
    Key: QTQAWLPCGQOSGP-KSRBKZBZBP
  • Key: QTQAWLPCGQOSGP-KSRBKZBZSA-N
  • 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
Properties
C29H40N2O9
Molar mass 560.64 g/mol
AppearanceGold-yellow fine crystalline powder
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Geldanamycin is a 1,4-benzoquinone ansamycin antitumor antibiotic that inhibits the function of Hsp90 (Heat Shock Protein 90) by binding to the unusual ADP/ATP-binding pocket of the protein. [1] HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis. [2]

Contents

Hsp90-geldanamycin complex. PDB 1yet 1yetgdm.png
Hsp90-geldanamycin complex. PDB 1yet

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. [4] These side effects have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position:

Biosynthesis

Geldanamycin was originally discovered in the organism Streptomyces hygroscopicus . [5] 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. [6] 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. [7]

Notes

  1. ↑ Schulte, T. W.; Akinaga, S.; Soga, S.; Sullivan, W.; Stensgard, B.; Toft, D.; Neckers, L. M. (1998). "Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin". Cell Stress & Chaperones. 3 (2): 100–108. doi:10.1379/1466-1268(1998)003<0100:ARBTTN>2.3.CO;2 (inactive 2024-04-26). PMC   312953 . PMID   9672245.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link)
  2. ↑ Wayne, N.; Mishra, P.; Bolon, D.N. (2011). "Hsp90 and Client Protein Maturation". Molecular Chaperones. Methods Mol Biol. Vol. 787. pp. 33–44. doi:10.1007/978-1-61779-295-3_3. ISBN   978-1-61779-294-6. PMC   5078872 . PMID   21898225.
  3. ↑ Stebbins, C. E.; Russo, A. A.; Schneider, C.; Rosen, N.; Hartl, F. U.; Pavletich, N. P. (1997). "Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent". Cell. 89 (2): 239–250. doi: 10.1016/S0092-8674(00)80203-2 . PMID   9108479. S2CID   5253110.
  4. ↑ Jilani, Kashif; Qadri, Syed M.; Lang, Florian (2013). "Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane". Cell Physiol Biochem. 32 (6): 1600–1609. doi: 10.1159/000356596 . PMID   24335345.
  5. ↑ He, W.; Wu, L.; Gao, Q.; Du, Y.; Wang, Y. (2006). "Identification of AHBA Biosynthetic Genes Related to Geldanamycin Biosynthesis in Streptomyces hygroscopicus 17997". Current Microbiology. 52 (3): 197–203. doi:10.1007/s00284-005-0203-y. PMID   16502293. S2CID   22291736.
  6. ↑ Kim, W.; Lee, D.; Hong, S. S.; Na, Z.; Shin, J. C.; Roh, S. H.; Wu, C. Z.; Choi, O.; Lee, K.; Shen, Y. M.; Paik, S. G.; Lee, J. J.; Hong, Y. S. (2009). "Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues". ChemBioChem. 10 (7): 1243–1251. doi:10.1002/cbic.200800763. PMID   19308924. S2CID   3273370.
  7. ↑ 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. H.; Lee, J. H.; Hong, Y. S.; Lee, J. J. (2006). "Biosynthesis of the Heat-Shock Protein 90 Inhibitor Geldanamycin: New Insight into the Formation of the Benzoquinone Moiety". ChemBioChem. 7 (2): 246–248. doi:10.1002/cbic.200500441. PMID   16381049. S2CID   42998903.

Related Research Articles

Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exposure to cold, UV light and during wound healing or tissue remodeling. Many members of this group perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress. This increase in expression is transcriptionally regulated. The dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF). HSPs are found in virtually all living organisms, from bacteria to humans.

<span class="mw-page-title-main">Hsp70</span> Family of heat shock proteins

The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for protein folding, performing chaperoning functions, and helping to protect cells from the adverse effects of physiological stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.

<span class="mw-page-title-main">Hsp90</span> Heat shock proteins with a molecular mass around 90kDa

Hsp90 is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs.

<span class="mw-page-title-main">Stress-induced-phosphoprotein 1</span> Protein-coding gene in the species Homo sapiens

Stress-induced-phosphoprotein 1 also Hsp70-Hsp90 organising protein (Hop) is encoded in the human by the STIP1 gene. It functions as a co-chaperone which reversibly links together the protein chaperones Hsp70 and Hsp90.

<span class="mw-page-title-main">Antimetabolite</span> Chemical that inhibits the use of a metabolite

An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used in chemotherapy for cancer.

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

Herbimycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 and alters its function. Hsp90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.

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

Radicicol, also known as monorden, is a natural product that binds to Hsp90 and alters its function. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.

<span class="mw-page-title-main">HSPA1A</span> Protein-coding gene in the species Homo sapiens

Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the HSPA1A gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. In addition, Hsp72 also facilitates DNA repair. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and inflammatory diseases such as Diabetes mellitus type 2 and rheumatoid arthritis.

<span class="mw-page-title-main">Heat shock protein 90kDa alpha (cytosolic), member A1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the HSP90AA1 gene.

<span class="mw-page-title-main">HSP90B1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the HSP90B1 gene.

<span class="mw-page-title-main">CDC37</span> Protein-coding gene in the species Homo sapiens

Hsp90 co-chaperone Cdc37 is a protein that in humans is encoded by the CDC37 gene. This protein is highly similar to Cdc 37, a cell division cycle control protein of Saccharomyces cerevisiae. This protein is a HSP90 Co-chaperone with specific function in cell signal transduction. It has been shown to form complex with Hsp90 and a variety of protein kinases including CDK4, CDK6, SRC, RAF1, MOK, as well as eIF-2 alpha kinases. It is thought to play a critical role in directing Hsp90 to its target kinases.

<span class="mw-page-title-main">HSP90AB1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein HSP 90-beta also called HSP90beta is a protein that in humans is encoded by the HSP90AB1 gene.

<span class="mw-page-title-main">PTGES3</span> Protein-coding gene in the species Homo sapiens

Prostaglandin E synthase 3 (cytosolic) is an enzyme that in humans is encoded by the PTGES3 gene.

<span class="mw-page-title-main">TNFAIP3</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor, alpha-induced protein 3 or A20 is a protein that in humans is encoded by the TNFAIP3 gene.

<span class="mw-page-title-main">ST13</span>

Hsc70-interacting protein also known as suppression of tumorigenicity 13 (ST13) is a protein that in humans is encoded by the ST13 gene.

<span class="mw-page-title-main">TRAP1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein 75 kDa, mitochondrial is a protein that in humans is encoded by the TRAP1 gene.

<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">GHKL domain</span> Evolutionary conserved protein domain

The GHKL domain is an evolutionary conserved protein domain. It is an ATPase domain found in several ATP-binding proteins such as histidine kinase, DNA gyrase B, topoisomerases, heat shock protein HSP90, phytochrome-like ATPases and DNA mismatch repair proteins.

<span class="mw-page-title-main">Hsp90 inhibitor</span> Drug class

An Hsp90 inhibitor is a substance that inhibits that activity of the Hsp90 heat shock protein. Since Hsp90 stabilizes a variety of proteins required for survival of cancer cells, these substances may have therapeutic benefit in the treatment of various types of malignancies. Furthermore, a number of Hsp90 inhibitors are currently undergoing clinical trials for a variety of cancers. Hsp90 inhibitors include the natural products geldanamycin, Retaspimycin hydrochloride and radicicol as well as semisynthetic derivatives 17-N-Allylamino-17-demethoxygeldanamycin (17AAG).

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

Luminespib is an experimental drug candidate for the treatment of cancer. It was discovered through a collaboration between The Institute of Cancer Research and the pharmaceutical company Vernalis and licensed to Novartis. From 2011 to 2014 it was in Phase II clinical trials. Chemically it is a resorcinylic isoxazole amide

References

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