Geldanamycin is a

1,4-benzoquinone 1,4-Benzoquinone, commonly known as ''para''-quinone, is a chemical compound with the formula C6H4O2. In a pure state, it forms bright-yellow crystals with a characteristic irritating odor, resembling that of chlorine, bleach, and hot plastic ...

ansamycin Ansamycins is a family of bacterial secondary metabolites that show antimicrobial activity against many Gram-positive and some Gram-negative bacteria, and includes various compounds, including streptovaricins and rifamycins. In addition, these c ...

antitumor antibiotic that inhibits the function of

Hsp90 Hsp90 (heat shock protein 90) 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, ...

(Heat Shock Protein 90) by binding to the unusual ADP/ATP-binding pocket of the protein. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and

oncogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

Geldanamycin induces the degradation of proteins that are mutated or overexpressed in

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

cells such as v-Src, Bcr-Abl,

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

, and

ERBB2 Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...

. This effect is mediated via HSP90. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate such as

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

, further, Jilani ''et al.''. reported that geldanamycin induces the apoptosis of

erythrocytes Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

under physiological concentrations. These side effects have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position: *

17-AAG Tanespimycin (17-''N''-allylamino-17-demethoxygeldanamycin, 17-AAG) is a derivative of the antibiotic geldanamycin that is being studied in the treatment of cancer, specifically in younger patients with certain types of leukemia or solid tumors, e ...

17-DMAG 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) is a chemical compound which is a semi-synthetic derivative of the antibiotic geldanamycin. It is being studied for the possibility of treating cancer. References Antibiotics M ...

Biosynthesis

Geldanamycin was originally discovered in the organism ''

Streptomyces hygroscopicus ''Streptomyces hygroscopicus'' is a bacterial species in the genus ''Streptomyces''. It was first described by Hans Laurits Jensen in 1931. Biochemistry Cultures of different strains of ''S. hygroscopicus'' can be used to produce a number of ...

''. It is a macrocyclic polyketide that is synthesized by a Type I

polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

. 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 Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and com ...

methylmalonyl-CoA Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle (aka the Citric Acid Cycle ...

, and methoxymalonyl-CoA to synthesize the precursor molecule Progeldanamycin. 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.

Notes

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

A comprehensive review about Geldanamycin, 17AAG and 17DMAG

Fermentek Fermentek Ltd. is a biotechnological company in the Atarot industrial zone of Jerusalem, Israel. It specializes in the research, development and manufacture of biologically active, natural products isolated from microorganisms as well as from ot ...

Geldanamycin from
Center for Pharmaceutical Research and Innovation
Geldanamycin bound to proteins
in the PDB 1,4-Benzoquinones Carbamates Lactams Phenol ethers Ethers Secondary alcohols Ansamycins