scholarly journals Epothilone D

2020 ◽  
Author(s):  
Keyword(s):  

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
J. A. Clark ◽  
J. A. Chuckowree ◽  
M. S. Dyer ◽  
T. C. Dickson ◽  
C. A. Blizzard


2001 ◽  
Vol 123 (23) ◽  
pp. 5407-5413 ◽  
Author(s):  
James D. White ◽  
Rich G. Carter ◽  
Kurt F. Sundermann ◽  
Markus Wartmann


2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Huimin Wang ◽  
Junheng Liang ◽  
Qianwen Yue ◽  
Long Li ◽  
Yan Shi ◽  
...  

Abstract Background Polyketide synthases (PKSs) include ketone synthase (KS), acyltransferase (AT) and acyl carrier protein (ACP) domains to catalyse the elongation of polyketide chains. Some PKSs also contain ketoreductase (KR), dehydratase (DH) and enoylreductase (ER) domains as modification domains. Insertion, deletion or substitution of the catalytic domains may lead to the production of novel polyketide derivatives or to the accumulation of desired products. Epothilones are 16-membered macrolides that have been used as anticancer drugs. The substrate promiscuity of the module 4 AT domain of the epothilone PKS (EPOAT4) results in production of epothilone mixtures; substitution of this domain may change the ratios of epothilones. In addition, there are two dormant domains in module 9 of the epothilone PKS. Removing these redundant domains to generate a simpler and more efficient assembly line is a desirable goal. Results The substitution of module 4 drastically diminished the activity of epothilone PKS. However, with careful design of the KS-AT linker and the post-AT linker, replacing EPOAT4 with EPOAT2, EPOAT6, EPOAT7 or EPOAT8 (specifically incorporating methylmalonyl-CoA (MMCoA)) significantly increased the ratio of epothilone D (4) to epothilone C (3) (the highest ratio of 4:3 = 4.6:1), whereas the ratio of 4:3 in the parental strain Schlegelella brevitalea 104-1 was 1.4:1. We also obtained three strains by swapping EPOAT4 with EPOAT3, EPOAT5, or EPOAT9, which specifically incorporate malonyl-CoA (MCoA). These strains produced only epothilone C, and the yield was increased by a factor of 1.8 compared to that of parental strain 104-1. Furthermore, mutations of five residues in the AT domain identified Ser310 as the critical factor for MMCoA recognition in EPOAT4. Then, the mutation of His308 to valine or tyrosine combined with the mutation of Phe310 to serine further altered the product ratios. At the same time, we successfully deleted the inactive module 9 DH and ER domains and fused the ΨKR domain with the KR domain through an ~ 25-residue linker to generate a productive and simplified epothilone PKS. Conclusions These results suggested that the substitution and deletion of catalytic domains effectively produces desirable compounds and that selection of the linkers between domains is crucial for maintaining intact PKS catalytic activity.



2018 ◽  
Vol 44 (6) ◽  
pp. 590-605 ◽  
Author(s):  
J. A. Clark ◽  
C. A. Blizzard ◽  
M. C. Breslin ◽  
E. J. Yeaman ◽  
K. M. Lee ◽  
...  




2011 ◽  
Vol 30 (4) ◽  
pp. 1676-1683 ◽  
Author(s):  
J. Paul Monk ◽  
Miguel Villalona-Calero ◽  
Joe Larkin ◽  
Greg Otterson ◽  
David S. Spriggs ◽  
...  


2018 ◽  
Vol 89 ◽  
pp. 80-94 ◽  
Author(s):  
Dario Valdinocci ◽  
Gary D. Grant ◽  
Tracey C. Dickson ◽  
Dean L. Pountney
Keyword(s):  


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Juan Jose Fernandez-Valenzuela ◽  
Raquel Sanchez-Varo ◽  
Clara Muñoz-Castro ◽  
Vanessa De Castro ◽  
Elisabeth Sanchez-Mejias ◽  
...  

Abstract In Alzheimer’s disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aβ) deposits. However, the effect of microtubule stabilizing agents on Aβ pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal Aβ accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Aβ levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and Aβ pathology.



2019 ◽  
Vol 98 ◽  
pp. 17-26 ◽  
Author(s):  
Tian-Qing Xiong ◽  
Ling-Meng Chen ◽  
Yue Gui ◽  
Tian Jiang ◽  
Bai-Hong Tan ◽  
...  


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