FR901512
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| Category | Enzyme inhibitors |
| Catalog number | BBF-05369 |
| CAS | 151606-25-6 |
| Molecular Weight | 376.44 |
| Molecular Formula | C21H28O6 |
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Description
FR901512, a new specific inhibitor of HMG-CoA reductase, is isolated from the culture of an agonomycetous fungus No. 14919. FR901512 inhibits cholesterol synthesis from [14C] acetate in Hep G2 cells.
Specification
| Synonyms | 6-Heptenoic acid, 7-[(6R,8S)-8-(acetyloxy)-5,6,7,8-tetrahydro-2,6-dimethyl-1-naphthalenyl]-3,5-dihydroxy-, (3R,5S,6E)-; (3R,5S,E)-7-((6R,8S)-8-acetoxy-2,6-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-3,5-dihydroxyhept-6-enoic acid |
| IUPAC Name | (E,3R,5S)-7-[(6R,8S)-8-acetyloxy-2,6-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl]-3,5-dihydroxyhept-6-enoic acid |
| Canonical SMILES | CC1CC(C2=C(C1)C=CC(=C2C=CC(CC(CC(=O)O)O)O)C)OC(=O)C |
| InChI | InChI=1S/C21H28O6/c1-12-8-15-5-4-13(2)18(21(15)19(9-12)27-14(3)22)7-6-16(23)10-17(24)11-20(25)26/h4-7,12,16-17,19,23-24H,8-11H2,1-3H3,(H,25,26)/b7-6+/t12-,16-,17-,19+/m1/s1 |
| InChI Key | CFHKAMNUJQAFGO-RFQUDDIJSA-N |
Properties
| Boiling Point | 608.9±55.0°C (Predicted) |
| Melting Point | 133.5°C |
| Density | 1.24±0.1 g/cm3 (Predicted) |
Reference Reading
1. Biosynthesis of Novel Statins by Combining Heterologous Genes from Xylaria and Aspergillus
Hiroya Itoh, Makoto Matsui, Yuki Miyamura, Itaru Takeda, Jun Ishii, Toshitaka Kumagai, Masayuki Machida, Takashi Shibata, Masanori Arita ACS Synth Biol. 2018 Dec 21;7(12):2783-2789. doi: 10.1021/acssynbio.8b00392. Epub 2018 Nov 13.
For many secondary metabolites, heterologous synthesis is the definitive step to determine their required biosynthetic genes. Using a multivector expression system in Saccharomyces cerevisiae, we reconstituted not only two natural statins from two fungal species, i.e., lovastatin from Aspergillus terreus and FR901512 from Xylaria grammica, but also new statin structures by mixing their genes. Combinatorial gene exchange experiments revealed the functional promiscuity of two polyketide synthases in A. terreus, lovB, and lovF; they could synthesize FR901512 with Xylaria genes. Key structure determinants of statins are essential accessory genes that are irreplaceable across species.
2. Search for transcription factors affecting productivity of the polyketide FR901512 in filamentous fungal sp. No. 14919 and identification of Drf1, a novel negative regulator of the biosynthetic gene cluster
Hiroya Itoh, Ai Miura, Itaru Takeda, Makoto Matsui, Koichi Tamano, Masayuki Machida, Takashi Shibata Biosci Biotechnol Biochem. 2019 Jun;83(6):1163-1170. doi: 10.1080/09168451.2019.1584519. Epub 2019 Mar 1.
In order to increase secondary metabolite production in filamentous fungi, a transcription factor gene in the biosynthetic gene cluster and global regulator genes such as laeA are considered plausible as targets for overexpression by genetic modification. In this study, we examined these overexpression effect in fungal sp. No. 14919 that produces FR901512, an HMG-CoA reductase inhibitor. Resultantly, the productivity was improved at 1.7-1.8 fold by overexpressing frlE, a transcription factor gene in the biosynthetic gene cluster, whereas productivity did not change by overexpression of laeA and veA. Furthermore, we searched for extra transcription factors affecting the productivity by transcriptome analysis between wild-type strain and highly productive UV mutants. After verifying productivity decrease by overexpression, Drf1, a novel transcription factor encoded by drf1 was identified as the negative regulator. Because each frlE product (FrlE) and Drf1 worked on the same cluster in positive and negative regulatory manners, their network was analyzed.
3. Knockout of the SREBP system increases production of the polyketide FR901512 in filamentous fungal sp. No. 14919 and lovastatin in Aspergillus terreus ATCC20542
Hiroya Itoh, Ai Miura, Makoto Matsui, Takayuki Arazoe, Keiji Nishida, Toshitaka Kumagai, Masanori Arita, Koichi Tamano, Masayuki Machida, Takashi Shibata Appl Microbiol Biotechnol. 2018 Feb;102(3):1393-1405. doi: 10.1007/s00253-017-8685-7. Epub 2017 Dec 21.
In the production of useful microbial secondary metabolites, the breeding of strains is generally performed by random mutagenesis. However, because random mutagenesis introduces many mutations into genomic DNA, the causative mutations leading to increased productivity are mostly unknown. Therefore, although gene targeting is more efficient for breeding than random mutagenesis, it is difficult to apply. In this study, a wild-type strain and randomly mutagenized strains of fungal sp. No. 14919, a filamentous fungus producing the HMG-CoA reductase inhibitor polyketide FR901512, were subjected to point mutation analysis based on whole genome sequencing. Among the mutated genes found, mutation of the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) had a positive effect on increasing FR901512 productivity. By complementing the SCAP gene in the SCAP-mutated strain, productivity was decreased to the level of the SCAP-intact strain. Conversely, when either the SCAP or SREBP gene was deleted, the productivity was significantly increased. By genomic transcriptional analysis, the expression levels of three enzymes in the ergosterol biosynthesis pathway were shown to be decreased by SCAP mutation. These findings led to the hypothesis that raw materials of polyketides, such as acetyl-CoA and malonyl-CoA, became more available for FR901512 biosynthesis due to depression in sterol biosynthesis caused by knockout of the SREBP system. This mechanism was confirmed in Aspergillus terreus producing the polyketide lovastatin, which is structurally similar to FR901512. Thus, knockout of the SREBP system should be considered significant for increasing the productivities of polyketides, such as HMG-CoA reductase inhibitors, by filamentous fungi.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
