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Dr. Yahu A. Liu Dr. Qihui Jin Qiang Ding Dr. Xueshi Hao Tingting Mo Shanshan Yan Dr. Yefen Zou Dr. Zhihong Huang Xiaoyue Zhang Wenqi Gao Dr. Tom Y.-H. Wu Chun Li Dr. Badry Bursalaya Dr. Michael Di Donato Dr. You-Qing Zhang Lisa Deaton Dr. Weijun Shen Dr. Brandon Taylor Anwesh Kamireddy Dr. George Harb Dr. Jing Li Dr. Yong Jia Dr. Andrew M. Schumacher Dr. Bryan Laffitte Dr. Richard Glynne Dr. Shifeng Pan Dr. Peter McNamara Dr. Valentina Molteni Dr. Jon Loren 《ChemMedChem》2020,15(16):1562-1570
Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation. 相似文献
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Shuko Terazawa Mariko Takada Yoriko Sato Hiroaki Nakajima Genji Imokawa 《International journal of molecular sciences》2021,22(4)
Little is known about the effects on hyaluronan (HA) metabolism of UVA radiation. This study demonstrates that the secretion of HA by human dermal fibroblasts (HDFs) is downregulated by UVA, accompanied by the down- and upregulation of mRNA and protein levels of the HA-synthesizing enzyme (HAS2) and the HA-degrading protein, HYaluronan Binding protein Involved in HA Depolymerization(HYBID), respectively. Signaling analysis revealed that the exposure distinctly elicits activation of the p38/MSK1/CREB/c-Fos/AP-1 axis, the JNK/c-Jun axis, and the p38/ATF-2 axis, but downregulates the phosphorylation of NF-kB and JAK/STAT3. A signal inhibition study demonstrated that the inhibition of p38 significantly abrogates the UVA-accentuated mRNA level of HYBID. Furthermore, the inhibition of STAT3 significantly downregulates the level of HAS2 mRNA in non-UVA exposed HDFs. Analysis using siRNAs demonstrated that transfection of ATF-2 siRNA but not c-Fos siRNA abrogates the increased protein level of HYBID in UVA-exposed HDFs. An inhibitor of protein tyrosine phosphatase but not of protein serine/threonine phosphatase restored the diminished phosphorylation level of STAT3 at Tyr 705, accompanied by a significant abolishing effect on the decreased mRNA expression level of HAS2. Silencing with a protein tyrosine phosphatase PTP-Meg2 siRNA revealed that it abrogates the decreased phosphorylation of STAT3 at Tyr 705 in UVA-exposed HDFs. These findings suggest that the UVA-induced decrease in HA secretion by HDFs is attributable to the down- and upregulation of HAS2 and HYBID expression, respectively, changes that are mainly ascribed to the inactivated signaling of the STAT3 axis due to the activated tyrosine protein phosphatase PTP-Meg2 and the activated signaling of the p38/ATF2 axis, respectively. 相似文献
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Inhibitors of Polyhydroxyalkanoate (PHA) Synthases: Synthesis,Molecular Docking,and Implications
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Dr. Wei Zhang Dr. Chao Chen Ruikai Cao Dr. Leila Maurmann Prof. Ping Li 《Chembiochem : a European journal of chemical biology》2015,16(1):156-166
Polyhydroxyalkanoate (PHA) synthases (PhaCs) catalyze the formation of biodegradable PHAs that are considered to be ideal alternatives to non‐biodegradable synthetic plastics. However, study of PhaCs has been challenging because the rate of PHA chain elongation is much faster than that of initiation. This difficulty, along with lack of a crystal structure, has become the main hurdle to understanding and engineering PhaCs for economical PHA production. Here we report the synthesis of two carbadethia CoA analogues—sT‐CH2‐CoA ( 26 a ) and sTet‐CH2‐CoA ( 26 b )—as well as sT‐aldehyde (saturated trimer aldehyde, 29 ), as new PhaC inhibitors. Study of these analogues with PhaECAv revealed that 26 a / b and 29 are competitive and mixed inhibitors, respectively. Both the CoA moiety and extension of PHA chain will increase binding affinity; this is consistent with our docking study. Estimation of the Kic values of 26 a and 26 b predicts that a CoA analogue incorporating an octameric hydroxybutanoate (HB) chain might facilitate the formation of a kinetically well‐behaved synthase. 相似文献
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Cover Feature: Directed Evolution of Hyaluronic Acid Synthase from Pasteurella multocida towards High‐Molecular‐Weight Hyaluronic Acid (ChemBioChem 13/2018)
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Christopher J. Schwalen Dr. Xinxin Feng Dr. Weidong Liu Bing O‐Dowd Dr. Tzu‐Ping Ko Christopher J. Shin Prof. Dr. Rey‐Ting Guo Prof. Dr. Douglas A. Mitchell Prof. Dr. Dr. Eric Oldfield 《Chembiochem : a European journal of chemical biology》2017,18(11):985-991
Many organisms contain head‐to‐head isoprenoid synthases; we investigated three such types of enzymes from the pathogens Neisseria meningitidis, Neisseria gonorrhoeae, and Enterococcus hirae. The E. hirae enzyme was found to produce dehydrosqualene, and we solved an inhibitor‐bound structure that revealed a fold similar to that of CrtM from Staphylococcus aureus. In contrast, the homologous proteins from Neisseria spp. carried out only the first half of the reaction, yielding presqualene diphosphate (PSPP). Based on product analyses, bioinformatics, and mutagenesis, we concluded that the Neisseria proteins were HpnDs (PSPP synthases). The differences in chemical reactivity to CrtM were due, at least in part, to the presence of a PSPP‐stabilizing arginine in the HpnDs, decreasing the rate of dehydrosqualene biosynthesis. These results show that not only S. aureus but also other bacterial pathogens contain head‐to‐head prenyl synthases, although their biological functions remain to be elucidated. 相似文献
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Drupes were handpicked from olive (Olea europaea L.) trees, cv chemlali, at 13 distinct stages of fruit development, referred to as weeks after flowering (WAF), and analyzed for their free and esterified sterols and triterpenoids content. These two classes of compounds are synthesized via the acetate/mevalonate pathway and share common precursors up to oxidosqualene (OS). Cyclization of OS in either cycloartenol or beta-amyrin constitutes a branch point between primary (sterol pathway) and secondary (triterpenoid pathway) metabolisms. At the onset of fruit development, i.e., between 12 and 18 WAF, drupes were found to contain high amounts of alpha- and beta-amyrins as well as more-oxygenated compounds such as triterpenic diols (erythrodiol and uvaol) and acids (oleanolic, ursolic and maslinic acids). Concomitantly, sterol precursors were barely detectable. From 21 WAF, when the olive fruit reached its final size and began to turn from green to purple, alpha- and beta-amyrins were no longer present, while 4,4-dimethyl- and 4alpha-methylsterols started to be formed, indicating a redirection of the carbon flux from the triterpenoid pathway towards the sterol pathway. Between 21 and 30 WAF, sterol end products, mainly represented by sitosterol, progressively accumulated and triterpenic diols were replaced by triterpenic acids, essentially maslinic acid. Interestingly, the developing olive fruit was found to accumulate significant amounts of parkeol as an ester conjugate. Whatever the stage of development, triterpenoids represent the major triterpenic compounds of the olive fruit. 相似文献