Archives of biochemistry and biophysics最新文献_第5页

Characterizations of angiotensin-converting enzyme-2 (ACE2) peptidase activity 血管紧张素转换酶-2（ACE2）肽酶活性的特征。

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2024-09-28 DOI: 10.1016/j.abb.2024.110167

Nathalie M. Saulnier, Devyn M. Thorne, Fariha E. Bablu, Alessia M. Suzuki, Rafa L. Khan, Katelin X. Oliveira, Yuichiro J. Suzuki

Angiotensin (Ang) II (1–8) is a potent vasoconstrictor known for its role in hypertension. Angiotensin-converting enzyme (ACE2) converts Ang II (1–8) to a vasodilator Ang (1–7) by removing the carboxy-terminal Phe. ACE2 more recently gained attention as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the coronavirus disease 2019 (COVID-19) pandemic. Given the pathophysiological importance of ACE2, the present study examined the mechanism of ACE2 catalytic activity by comparing the ability of angiotensin molecules of various lengths to compete with the artificial fluorogenic substrate. The Fluorimetric SensoLyte 390 ACE2 Activity Assay uses an Mca/Dnp fluorescence resonance energy transfer peptide as the substrate. Results showed that the natural substrate Ang II (1–8) competed with the fluorogenic substrate, reducing the fluorescence signals. Deletion of C-terminal Phe resulted in the loss of the ability to compete with the artificial substrate, as shown by the actions of Ang (1–7), Ang (2–7), and Ang (5–7). By contrast, the loss of N-terminal Asp potentiated the ability to compete with the substrate as seen by the action of Ang III (2–8). However, the loss of two amino acids (Asp-Arg) from the N-terminus reduced the ability to compete with the substrate as observed by the actions of Ang IV (3–8) and Ang (5–8). Ang I (1–10) and Ang (1–9) did not strongly compete with the substrate. Interestingly, shorter peptides Ang (1–5) and Ang (1–4) potentiated the ACE2 activity. These results suggest that Ang II and Ang III are the best natural substrates for ACE2.

血管紧张素（Ang）II（1-8）是一种强效的血管收缩剂，因其在高血压中的作用而闻名。血管紧张素转换酶（ACE2）通过去除羧基末端的 Phe，将 Ang II（1-8）转换为血管扩张剂 Ang（1-7）。最近，ACE2 作为导致 2019 年冠状病毒病（COVID-19）大流行的严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）的受体而受到关注。鉴于 ACE2 在病理生理学方面的重要性，本研究通过比较不同长度的血管紧张素分子与人工荧光底物竞争的能力，研究了 ACE2 催化活性的机制。荧光测定 SensoLyte 390 ACE2 活性测定法使用 Mca/Dnp 荧光共振能量转移肽作为底物。结果显示，天然底物 Ang II（1-8）与荧光底物竞争，减少了荧光信号。从 Ang (1-7)、Ang (2-7) 和 Ang (5-7) 的作用中可以看出，删除 C 端 Phe 会导致失去与人工底物竞争的能力。相比之下，N 端 Asp 的缺失增强了与底物竞争的能力，如 Ang III 的作用（2-8）所示。然而，从 Ang IV（3-8）和 Ang（5-8）的作用中可以看出，从 N 端损失两个氨基酸（Asp-Arg）会降低与底物竞争的能力。Ang I（1-10）和 Ang（1-9）与底物的竞争性不强。有趣的是，短肽 Ang (1-5) 和 Ang (1-4) 能增强 ACE2 的活性。这些结果表明，Ang II 和 Ang III 是 ACE2 的最佳天然底物。

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引用次数: 0

Anionic cardiolipin stabilizes the transmembrane region of hyaluronan synthase and promotes catalysis-relevant dynamics 阴离子心磷脂能稳定透明质酸合成酶的跨膜区域，并促进催化相关的动态变化。

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2024-09-25 DOI: 10.1016/j.abb.2024.110165

Kaiyi Zhu, Yilei Han, Yupei Jian, Guoqiang Jiang, Diannan Lu, Zheng Liu

Hyaluronic acid (HA) is a glycosaminoglycan essential for cellular processes and finding increasingly applications in medicine, pharmaceuticals, and cosmetics. While membrane-integrated Class I hyaluronan synthase (HAS) catalyzes HA synthesis in most organisms, the molecular mechanisms by which HAS-lipid interactions impact HAS catalysis remain unclear. This study employed coarse-grained molecular dynamics simulation combined with dimensionality reduction to uncover the interplay between lipids and Streptococcus equisimilis HAS (SeHAS). A minimum of 67 % cardiolipin is necessary for HA synthesis, as determined through simulations using gradient-composed membranes. The anionic cardiolipin stabilizes the cationic transmembrane regions of SeHAS and thereby maintains its conformation. Moreover, the highly dynamic cardiolipin is required to modulate the catalysis-relevant motions in HAS and thus facilitate HA synthesis. These findings provide molecular insights essential not only for understanding the physiological functions of HAS, but also for the development of cell factories and enzyme catalysts for HA production.

透明质酸（HA）是一种对细胞过程至关重要的糖胺聚糖，在医学、制药和化妆品领域的应用日益广泛。在大多数生物体内，膜整合 I 类透明质酸合成酶（HAS）催化 HA 的合成，但 HAS 与脂质相互作用影响 HAS 催化的分子机制仍不清楚。本研究采用粗粒度分子动力学模拟结合降维技术，揭示了脂质与马氏链球菌 HAS（SeHAS）之间的相互作用。通过梯度膜模拟确定，HA 合成至少需要 67% 的心磷脂。阴离子心磷脂能稳定 SeHAS 的阳离子跨膜区域，从而保持其构象。此外，高动态的心磷脂需要调节 HAS 中与催化相关的运动，从而促进 HA 的合成。这些发现不仅为了解 HAS 的生理功能提供了重要的分子见解，也为开发用于生产 HA 的细胞工厂和酶催化剂提供了重要依据。

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引用次数: 0

Harnessing marine natural products to inhibit PAD4 triple mutant: A structure-based virtual screening approach for rheumatoid arthritis therapy 利用海洋天然产物抑制 PAD4 三重突变体：基于结构的类风湿关节炎治疗虚拟筛选方法。

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2024-09-24 DOI: 10.1016/j.abb.2024.110164

Santhiya Panchalingam , Manikandan Jayaraman , Jeyakanthan Jeyaraman , Govindaraju Kasivelu

Peptidylarginine deiminase type4 (PAD4) is a pivotal pro-inflammatory protein within the human immune system, intricately involved in both inflammatory processes and immune responses. Its role extends to the generation of diverse immune cell types, including T cells, B cells, natural killer cells, and dendritic cells. PAD4 has recently garnered attention due to its association with a spectrum of inflammatory and autoimmune disorders, notably rheumatoid arthritis (RA). Mutations in the PAD4 gene, leading to the conversion of arginine to citrulline, have emerged as significant factors in the pathogenesis of RA and related conditions. As a calcium-dependent enzyme, PAD4 is central to the citrullination process, a crucial post-translational modification implicated in disease pathophysiology. Its critical role in autoimmune disorders and inflammation makes PAD4 a prime candidate for therapeutic intervention in RA. Inhibiting PAD4 presents a promising avenue for mitigating inflammatory responses and curtailing joint degradation and impairment. To explore its therapeutic potential, a structure-based virtual screening (SBVS) approach was employed, harnessing an array of marine natural products (MNPs) sourced from databases such as CMNPD, MNPD, and Seaweed. Notably, MNPD10752, CMNPD12680, and CMNPD2751 emerged as potential hit molecules, exhibiting adherence to essential pharmacokinetic properties and favorable toxicity profiles. Quantum mechanics studies using density functional theory (DFT) calculations revealed the inhibitory potential of these identified natural products. Further structural elucidation through molecular dynamics simulations (MDS) and principal component-based free energy landscape (FEL) analysis shed light on the stability of MNP-bound PAD4 complexes. In conclusion, this computational study serves as a stepping stone for further experimental evaluation, aiming to explore the potential of MNPs in addressing PAD4-related human pathologies.

肽基精氨酸脱氨酶 4 型（PAD4）是人体免疫系统中一种关键的促炎症蛋白，密切参与炎症过程和免疫反应。它的作用延伸到多种免疫细胞类型的生成，包括 T 细胞、B 细胞、自然杀伤细胞和树突状细胞。最近，PAD4 因其与一系列炎症和自身免疫性疾病，尤其是类风湿性关节炎（RA）的关联而备受关注。PAD4 基因突变会导致精氨酸转化为瓜氨酸，已成为类风湿性关节炎及相关疾病发病机制的重要因素。作为一种钙依赖性酶，PAD4 是瓜氨酸化过程的核心，而瓜氨酸化是一种关键的翻译后修饰，与疾病的病理生理学有关。它在自身免疫性疾病和炎症中的关键作用使 PAD4 成为对 RA 进行治疗干预的主要候选对象。抑制 PAD4 为减轻炎症反应、遏制关节退化和损伤提供了一条很有前景的途径。为了探索其治疗潜力，我们采用了一种基于结构的虚拟筛选（SBVS）方法，利用了来自 CMNPD、MNPD 和 Seaweed 等数据库的一系列海洋天然产物（MNPs）。值得注意的是，MNPD10752、CMNPD12680 和 CMNPD2751 成为潜在的命中分子，它们表现出基本的药代动力学特性和良好的毒性特征。利用密度泛函理论（DFT）计算进行的量子力学研究揭示了这些已确定的天然产物的抑制潜力。通过分子动力学模拟 (MDS) 和基于主成分的自由能谱 (FEL) 分析进一步阐明了 MNP 结合 PAD4 复合物的稳定性。总之，这项计算研究为进一步的实验评估奠定了基础，旨在探索 MNPs 解决 PAD4 相关人类病症的潜力。

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引用次数: 0

Synthesis of N-substituted 4-phenyl-2-aminothiazole derivatives and investigation of their inhibition properties against hCA I, II, and AChE enzymes N-取代的 4-苯基-2-氨基噻唑衍生物的合成及其对 hCA I、II 和 AChE 酶抑制特性的研究

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2024-09-24 DOI: 10.1016/j.abb.2024.110159

Abdullah Biçer , Cüneyt Çağlayan , Yeliz Demir , Cüneyt Türkeş , Ramazan Altundaş , Hasan Akyıldız , Şükrü Beydemir

In this study, thiazole derivatives containing sulphonamide, amide, and phenyl amino groups were synthesized to protect the free amino groups of 5-methyl-4-phenyl-2-aminothiazole and 4-phenyl-2-aminothiazole. Halogenated reactions of N-protected thiazole derivatives have been investigated. LCMS, FT-IR, ¹H NMR, and ¹³C NMR spectroscopy techniques were used to elucidate the structures of the synthesized compounds. Inhibition effects of the N-protected thiazole derivatives against human carbonic anhydrase I, II (hCA I, hCA II), and acetylcholinesterase (AChE) were investigated. The best results among the synthesized N-protected thiazole derivatives showed K_i values in the range of 46.85–587.53 nM against hCA I, 35.01–578.06 nM against hCA II, and in the range of 19.58–226.18 nM against AChE. Furthermore, in silico studies with the target enzyme of the thiazole derivatives (9 and 11), which showed the best results experimentally, have examined the binding interactions of the related compounds at the enzyme active site.

本研究合成了含有磺酰胺、酰胺和苯基氨基的噻唑衍生物，以保护 5-甲基-4-苯基-2-氨基噻唑和 4-苯基-2-氨基噻唑的游离氨基。研究了 N 保护噻唑衍生物的卤化反应。利用 LCMS、FT-IR、1H NMR 和 13C NMR 光谱技术阐明了合成化合物的结构。研究了 N 保护噻唑衍生物对人碳酸酐酶 I、II（hCA I、hCA II）和乙酰胆碱酯酶（AChE）的抑制作用。合成的 N-保护噻唑衍生物中效果最好的对 hCA I 的 Ki 值范围为 46.85-587.53 nM，对 hCA II 的 Ki 值范围为 35.01-578.06 nM，对 AChE 的 Ki 值范围为 19.58-226.18 nM。此外，通过对实验结果最好的噻唑衍生物（9 和 11）的目标酶进行硅学研究，考察了相关化合物在酶活性位点的结合相互作用。

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引用次数: 0

Probing the site of glutathione reduction by thioredoxin/glutathione reductase from Schistosoma mansoni under anaerobic conditions 探究厌氧条件下曼氏血吸虫硫氧还蛋白/谷胱甘肽还原酶还原谷胱甘肽的部位

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2024-09-23 DOI: 10.1016/j.abb.2024.110162

Tyler B. Alt, Madison M. Smith, Graham R. Moran

Thioredoxin/glutathione reductase from Schistosoma mansoni (SmTGR) is a multifunctional enzyme that catalyzes the reduction of glutathione (GSSG) and thioredoxin, as well as the deglutathionylation of peptide and non-peptide substrates. SmTGR structurally resembles known glutathione reductases (GR) and thioredoxin reductases (TrxR) but with an appended N-terminal domain that has a typical glutaredoxin (Grx) fold. Despite structural homology with known GRs, the site of GSSG reduction has frequently been reported as the Grx domain, based primarily on aerobic, steady-state kinetic measurements and x-ray crystallography. Here, we present an anaerobic characterization of a series of variant SmTGRs to establish the site of GSSG reduction as the cysteine pair most proximal to the FAD, Cys154/Cys159, equivalent to the site of GSSG reduction in GRs. Anaerobic steady-state analysis of U597C, U597S, U597C + C31S, and I592STOP SmTGR demonstrate that the Grx domain is not involved in the catalytic reduction of GSSG, as redox silencing of the C-terminus results in no modulation of the observed turnover number (∼0.025 s⁻¹) and redox silencing of the Grx domain results in an increased observed turnover number (∼0.08 s⁻¹). Transient-state single turnover analysis of these variants corroborates this, as the slowest rate observed titrates hyperbolically with GSSG concentration and approaches a limit that coincides with the respective steady-state turnover number for each variant. Numerical integration fitting of the transient state data can only account for the observed trends when competitive binding of the C-terminus is included, indicating that the partitioning of electrons to either substrate occurs at the Cys154/Cys159 disulfide rather than the previously proposed Cys596/Sec597 sulfide/selenide. Paradoxically, truncating the C-terminus at Ile592 results in a loss of GR activity, indicating a crucial non-redox role for the C-terminus.

曼氏血吸虫的硫氧还原酶/谷胱甘肽还原酶（SmTGR）是一种多功能酶，可催化谷胱甘肽（GSSG）和硫氧还原酶的还原，以及肽和非肽底物的脱谷胱甘肽化。SmTGR 在结构上类似于已知的谷胱甘肽还原酶（GR）和硫氧还原酶（TrxR），但其 N 端结构域具有典型的谷胱甘肽还原酶（Grx）折叠。尽管与已知的 GR 存在结构同源性，但 GSSG 的还原位点经常被报告为 Grx 结构域，这主要是基于有氧、稳态动力学测量和 X 射线晶体学。在这里，我们对一系列变体 SmTGRs 进行了厌氧表征，以确定 GSSG 还原位点是最靠近 FAD 的半胱氨酸对 Cys154/Cys159，相当于 GRs 中的 GSSG 还原位点。对 U597C、U597S、U597C + C31S 和 I592STOP SmTGR 的厌氧稳态分析表明，Grx 结构域不参与 GSSG 的催化还原，因为 C 端氧化还原沉默不会改变观察到的周转次数（∼0.025 s-1），而 Grx 结构域氧化还原沉默会导致观察到的周转次数增加（∼0.08 s-1）。对这些变体的瞬态单一周转分析证实了这一点，因为观察到的最慢速率随 GSSG 浓度呈双曲线滴定，并接近与每个变体各自的稳态周转次数相吻合的极限。对瞬态数据的数值积分拟合只能在包括 C 端竞争性结合的情况下才能解释观察到的趋势，这表明电子到两种底物的分配发生在 Cys154/Cys159 二硫化物处，而不是之前提出的 Cys596/Sec597 硫化物/硒化物处。矛盾的是，在 Ile592 处截断 C 端会导致 GR 活性丧失，这表明 C 端具有关键的非氧化还原作用。

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引用次数: 0

Niacin-induced flushing: Mechanism, pathophysiology, and future perspectives 烟酸诱导的潮红：机制、病理生理学和未来展望

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2024-09-23 DOI: 10.1016/j.abb.2024.110163

Aaqib Javaid , Shyam Lal Mudavath

Flushing is a typical physiological reaction to high emotional reactions. It is characterized by cutaneous vasodilation and a feeling of warmth and skin redness, especially in the face areas. Flushing is frequently linked to social anxiety, but it can also be a sign of a number of benign and malignant medical disorders. The study focuses on niacin-induced flushing, a well-researched side effect of the niacin, a drug which increases cholesterol levels. Niacin-induced flushing occurs when the hydroxycarboxylic acid receptor 2 (HCA2 or GPR109A) is activated. This starts a signaling cascade that releases prostaglandins, especially PGD2, which causes cutaneous vasodilation. Furthermore, niacin directly interacts with the transient receptor potential (TRP) channel TRPV1, offering a different, non-prostaglandin-based explanation for flushing brought on by niacin, highlighting the intricate physiological mechanisms behind this widespread occurrence. The review delves deeper into the advantages of niacin treatment for the cardiovascular system, highlighting how it can improve lipid profiles and lower cardiovascular events when used with statins. To sum it up, this study offers a thorough understanding of flushing, including its physiological foundation, many etiologies, diagnostic difficulties, and the subtleties of flushing caused by niacin. The investigation of innovative dose forms and nanomedicine highlights the continuous endeavors to improve patient compliance and reduce side effects, laying the groundwork for further developments in flushing treatment.

脸红是情绪激动时的一种典型生理反应。其特点是皮肤血管扩张，感觉发热和皮肤发红，尤其是脸部。脸红经常与社交焦虑有关，但也可能是一些良性和恶性疾病的征兆。这项研究的重点是烟酸诱发的脸红，这是烟酸的一种副作用，已得到充分研究，烟酸是一种能提高胆固醇水平的药物。当羟基羧酸受体 2（HCA2 或 GPR109A）被激活时，烟酸会诱发潮红。这会启动一个信号级联，释放前列腺素，尤其是 PGD2，从而导致皮肤血管扩张。此外，烟酸直接与瞬时受体电位（TRP）通道 TRPV1 相互作用，为烟酸引起的潮红提供了一种不同的、非基于前列腺素的解释，突出了这一普遍现象背后错综复杂的生理机制。综述深入探讨了烟酸治疗对心血管系统的优势，强调了烟酸与他汀类药物一起使用时如何改善血脂状况和降低心血管事件。总之，本研究对潮红有了全面的了解，包括其生理基础、多种病因、诊断困难以及烟酸引起潮红的微妙之处。对创新剂型和纳米药物的研究凸显了为提高患者依从性和减少副作用所做的不懈努力，为潮红治疗的进一步发展奠定了基础。

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引用次数: 0

Aldose reductase with quinolone antibiotics interaction: In vitro and in silico approach of its relationship with diabetic complications 醛糖还原酶与喹诺酮类抗生素的相互作用：体外和硅学方法研究其与糖尿病并发症的关系。

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2024-09-21 DOI: 10.1016/j.abb.2024.110161

Cüneyt Türkeş

Aldose reductase (AR, EC1.1.1.21), a member of the aldo-keto reductase family, is critically implicated in the pathogenesis of chronic complications associated with diabetes mellitus, including neuropathy, nephropathy, and retinopathy. Hyperglycemia-induced AR overactivity results in intracellular sorbitol accumulation, NADPH depletion, and oxidative stress. Consequently, AR is recognized as a key mediator of oxidative and inflammatory signaling pathways involved in diverse human pathologies such as cardiovascular diseases, inflammatory disorders, and cancer. This has sparked renewed interest in developing novel AR inhibitors (ARIs) with enhanced therapeutic profiles. In this study, we evaluated the inhibitory potential of five quinolone antibiotics-gatifloxacin, lomefloxacin, nalidixic acid, norfloxacin, and sparfloxacin-as ARIs relevant to various physiological and pathological conditions. Through comprehensive in vitro and in silico analyses, we explored these antibiotics' binding interactions and affinities within the AR active site. Our findings reveal that these quinolones moderately inhibit AR at micromolar concentrations, with inhibition constants (K_Is) ranging from 1.03 ± 0.13 μM to 4.12 ± 0.51 μM, compared to the reference drug epalrestat (K_I of 0.85 ± 0.06 μM). The combined in vitro and in silico results underscore significant interactions between these drugs and AR, suggesting their potential as therapeutic agents against the aforementioned pathological conditions. Furthermore, these insights will aid in optimizing clinical dosing regimens and mitigating unexpected drug-drug interactions when these antibiotics are co-administered with other treatments.

醛糖还原酶（AR，EC1.1.1.21）是醛酮还原酶家族的成员之一，与糖尿病相关慢性并发症（包括神经病变、肾病变和视网膜病变）的发病机制密切相关。高血糖诱导的 AR 过度活跃会导致细胞内山梨醇积聚、NADPH 耗竭和氧化应激。因此，AR 被认为是氧化和炎症信号通路的关键介质，涉及心血管疾病、炎症性疾病和癌症等多种人类病症。这再次激发了人们对开发新型 AR 抑制剂（ARIs）的兴趣。在本研究中，我们评估了五种喹诺酮类抗生素--加替沙星、洛美沙星、萘啶酸、诺氟沙星和司帕沙星--作为与各种生理和病理条件相关的 ARIs 的抑制潜力。通过全面的体外和硅学分析，我们探索了这些抗生素与 AR 活性位点的结合相互作用和亲和力。我们的研究结果表明，这些喹诺酮类药物在微摩尔浓度下对AR有中度抑制作用，抑制常数（KIs）从1.03 ± 0.13 μM到4.12 ± 0.51 μM不等，而参比药物依帕司他（KI为0.85 ± 0.06 μM）的抑制常数为0.85 ± 0.06 μM。综合体外研究和硅学研究结果，这些药物与AR之间的相互作用非常明显，表明它们有可能成为治疗上述病症的药物。此外，这些见解将有助于优化临床用药方案，并在这些抗生素与其他疗法联合用药时减少意外的药物相互作用。

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引用次数: 0

SHIN-2 exerts potent activity against VanA-type vancomycin-resistant Enterococcus faecium in vitro by stabilizing the active site loop of serine hydroxymethyltransferase SHIN-2 通过稳定丝氨酸羟甲基转移酶的活性位点环路，在体外对耐 VanA 型万古霉素的粪肠球菌发挥强效活性。

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2024-09-21 DOI: 10.1016/j.abb.2024.110160

Hironori Hayashi , Erika Saijo , Kazushige Hirata , Shumei Murakami , Haruka Okuda , Eiichi N. Kodama , Kazuya Hasegawa , Kazutaka Murayama

Novel classes of antibiotics are needed to improve the resilience of the healthcare system to antimicrobial resistance (AMR), including vancomycin resistance. vanA gene cluster is a cause of vancomycin resistance. This gene cluster is transferred and spreads vancomycin resistance from Enterococcus spp. to Staphylococcus aureus. Therefore, novel antibacterial agents are required to combat AMR, including vanA-type vancomycin resistance. Serine hydroxymethyltransferase (SHMT) is a key target of antibacterial agents. However, the specific binding mechanisms of SHMT inhibitors remain unclear. Detailed structural information will contribute to understanding these mechanisms. In this study, we found that (+)–SHIN–2, the first in vivo active inhibitor of human SHMT, is strongly bound to the Enterococcus faecium SHMT (efmSHMT). Comparison of the crystal structures of apo- and (+)–SHIN–2-boud efmSHMT revealed that (+)–SHIN–2 stabilized the active site loop of efmSHMT via hydrogen bonds, which are critical for efmSHMT inhibition. Additionally, (+)–SHIN–2 formed hydrogen bonds with serine, forming the Schiff's base with pyridoxal 5′-phosphate, which is a co-factor of SHMT. Furthermore, (+)–SHIN–2 exerted biostatic effects on vancomycin-susceptible and vanA-type vancomycin-resistant E. faecium in vitro, indicating that SHMT inhibitors do not induce cross-resistance to vanA-type vancomycin. Overall, these findings can aid in the design of novel SHMT inhibitors to combat AMR, including vancomycin resistance.

需要新型抗生素来提高医疗保健系统对抗菌素耐药性（AMR）（包括万古霉素耐药性）的抵抗力。该基因簇可将万古霉素耐药性从肠球菌转移到金黄色葡萄球菌。因此，需要新型抗菌剂来对抗 AMR，包括 VanA 型万古霉素耐药性。丝氨酸羟甲基转移酶（SHMT）是抗菌药的一个关键靶点。然而，SHMT 抑制剂的具体结合机制仍不清楚。详细的结构信息将有助于了解这些机制。本研究发现，(+)-SHIN-2 是人类 SHMT 的首个体内活性抑制剂，能与粪肠球菌 SHMT（efmSHMT）强结合。通过比较apo-和(+)-SHIN-2-boud efmSHMT的晶体结构发现，(+)-SHIN-2通过氢键稳定了efmSHMT的活性位点环，这对efmSHMT的抑制作用至关重要。此外，(+)-SHIN-2 还与丝氨酸形成氢键，与作为 SHMT 辅因子的 5'- 磷酸吡哆醛形成希夫碱。此外，(+)-SHIN-2 还能在体外对万古霉素敏感和万古霉素耐药的粪肠球菌产生生物静电效应，表明 SHMT 抑制剂不会诱发对万古霉素的交叉耐药性。总之，这些发现有助于设计新型 SHMT 抑制剂，以对抗包括万古霉素耐药性在内的 AMR。

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引用次数: 0

Discovering potential asthma therapeutics targeting hematopoietic prostaglandin D2 synthase: An integrated computational approach 发现针对造血前列腺素 D2 合成酶的潜在哮喘疗法：综合计算方法。

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2024-09-20 DOI: 10.1016/j.abb.2024.110157

Fahad M. Aldakheel

Allergic asthma, a chronic inflammatory illness that affects millions worldwide, has serious economic and health consequences. Despite advances in therapy, contemporary treatments have poor efficacy and negative effects. This study investigates hematopoietic prostaglandin D2 synthase (HPGDS) as a potential target for novel asthma therapies. Targeting HPGDS may provide innovative treatment methods. A library of phytochemicals was used to find putative HPGDS inhibitors by structure-based and ligand-based virtual screening. Among the 2295 compounds screened, four compounds (ZINC208828240, ZINC95627530, ZINC14727536, and ZINC14711790) demonstrated strong binding affinities of −10.4, −10.3, −9.2, −9.1 kcal/mol respectively with key residues, suggesting their potential as a highly effective HPGDS inhibitor. Molecular dynamics (MD) simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) computations were further performed to evaluate the stability and binding affinity of the complexes. MD simulations and MMPBSA confirmed that compound ZINC14711790 showed high stability and binding affinity (binding energy −31.52 kcal/mol) than other compounds, including HQL-79, suggesting that this compound might be used as promising inhibitors to treat asthma. RMSD and RMSF analysis also revealed that ZINC14711790 exhibited strong dynamic stability. The findings of this study show the efficacy of ZINC14711790 as HPGDS inhibitors with high binding affinity, dynamic stability, and appropriate ADMET profile.

过敏性哮喘是一种影响全球数百万人的慢性炎症性疾病，对经济和健康造成严重后果。尽管治疗手段在不断进步，但当代疗法的疗效不佳且存在负面影响。本研究将造血前列腺素 D2 合成酶（HPGDS）作为新型哮喘疗法的潜在靶点。以 HPGDS 为靶点可提供创新的治疗方法。通过基于结构和配体的虚拟筛选，我们利用植物化学物质文库找到了潜在的 HPGDS 抑制剂。在筛选出的 2295 个化合物中，4 个化合物（ZINC208828240、ZINC95627530、ZINC14727536 和 ZINC14711790）与关键残基的结合亲和力分别为 -10.4、-10.3、-9.2、-9.1 kcal/mol，表明它们具有作为高效 HPGDS 抑制剂的潜力。研究人员进一步进行了分子动力学（MD）模拟和分子力学泊松-波尔兹曼表面积（MMPBSA）计算，以评估复合物的稳定性和结合亲和力。MD 模拟和 MMPBSA 证实，与包括 HQL-79 在内的其他化合物相比，ZINC14711790 复合物表现出较高的稳定性和结合亲和力（结合能 -31.52 kcal/mol），这表明该化合物有望用作治疗哮喘的抑制剂。RMSD 和 RMSF 分析还显示 ZINC14711790 具有很强的动态稳定性。这项研究结果表明，ZINC14711790 作为 HPGDS 抑制剂具有高结合亲和力、动态稳定性和适当的 ADMET 特征。

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引用次数: 0

Regulation of corticosteroid-binding globulin release in murine leydig tumor cell line mLTC-1 by luteinizing hormone and interleukin-6 促黄体生成素和白细胞介素-6对小鼠莱地格肿瘤细胞系 mLTC-1 中皮质类固醇结合球蛋白释放的调节。

IF 3.8 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics

Pub Date : 2024-09-20 DOI: 10.1016/j.abb.2024.110158

Yuxin Zhang, Lei Liu, Chunyu Yang, Wei Xie, Jianshe Wang

Exogenous assaults interfere with homeostatic processes in the body by inducing stress responses. Corticosteroid-binding globulin (CBG) binds to stress hormone glucocorticoids to transport and dynamically control their availability to target tissues. In our previous study, we confirmed that CBG is locally produced by Leydig cells in the testes. Here, we explored the potential regulators of CBG using a murine Leydig tumor cell line (mLTC-1). Results indicated that luteinizing hormone (LH) and interleukin-6 (IL-6) were important factors stimulating the release of CBG from mLTC-1 cells. In addition, IL-6 stimulated mLTC-1 cells to release alpha-1 antitrypsin (AAT), a serine proteinase inhibitor (serpin) that affects CBG conformation. The results implied that any challenge that altered LH or IL-6 levels also changed the release and binding status of CBG with steroid hormones in the testicular microenvironment and modulated cellular responses to these stress hormones. In addition, secretory proteomic analysis indicated that the extracellular matrix (ECM), cytoskeleton, and proteasomes were essentially produced by the mLTC-1 cells, and LH evoked the secretion of proteins involved in binding and metabolism. These results emphasize that Leydig cells may undertake more functions than just steroidogenesis, and the regulation of Leydig cells by LH is versatile.

外源性攻击通过诱导应激反应干扰体内平衡过程。皮质类固醇结合球蛋白（CBG）能与应激激素糖皮质激素结合，运输并动态控制目标组织的糖皮质激素供应。在我们之前的研究中，我们证实了 CBG 是由睾丸中的 Leydig 细胞在局部产生的。在此，我们利用小鼠雷迪格肿瘤细胞系（mLTC-1）探索了CBG的潜在调节因子。结果表明，促黄体生成素（LH）和白细胞介素-6（IL-6）是刺激 mLTC-1 细胞释放 CBG 的重要因素。此外，IL-6 还刺激 mLTC-1 细胞释放α-1 抗胰蛋白酶（AAT），这是一种丝氨酸蛋白酶抑制剂（serpin），会影响 CBG 的构象。结果表明，任何改变 LH 或 IL-6 水平的挑战也会改变睾丸微环境中 CBG 与类固醇激素的释放和结合状态，并调节细胞对这些应激激素的反应。此外，分泌蛋白组学分析表明，细胞外基质（ECM）、细胞骨架和蛋白酶体基本上是由 mLTC-1 细胞产生的，LH 诱导了参与结合和代谢的蛋白质的分泌。这些结果表明，Leydig细胞可能不仅仅承担类固醇生成的功能，LH对Leydig细胞的调控是多方面的。

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引用次数: 0