跨膜丝氨酸蛋白酶6：一种新发现的铁调素调节子

跨膜丝氨酸蛋白酶6(TMPRSS6)是最近发现的一种丝氨酸蛋白激酶,它通过调节铁调素(hepcidin)的表达,进而影响生物机体的铁稳态.它的发现,不仅对进一步认识机体铁代谢的调控及其分子机制有重要的理论意义,还为揭示铁代谢相关疾病的病因和探索治疗的相关途径提供了新的思路.     

前列腺癌中TMPRSS2-ETS基因融合及机制研究进展

超过50%的前列腺癌中存在跨膜丝氨酸蛋白酶2(TMPRSS2)和E26(ETS)转录因子间的基因融合,其中TMPRSS2-ERG最为常见。TMPRSS2-ERG基因融合造成的ERG过表达参与了前列腺的癌变。雄激素受体结合和遗传毒性胁迫共同诱导了染色体的靠近和TMPRSS2-ETS的基因融合。TMPRSS2-ERG基因融合可作为前列腺癌诊断的一种生物标志物,并可通过病人尿液检测来实现。文章对TMPRSS2-ETS基因融合的特征、融合及致癌及临床应用进行了综述。     

跨膜丝氨酸蛋白酶2在病毒感染中的作用及其抑制剂的研究进展

跨膜丝氨酸蛋白酶2(transmembrane serine proteinase 2,TMPRSS2)是细胞膜表面丝氨酸蛋白酶家族的一员,它具有介导冠状病毒棘突蛋白水解的作用,为冠状病毒感染宿主必需的宿主蛋白。现就近年来TMPRSS2在分子生物学功能方面的研究;TMPRSS2在呼吸系统病毒感染,尤其是在冠状病毒感染中的作用,以及以TMPRSS2为靶点的药物研究进展作一概述,旨在对冠状病毒特别是新冠病毒的预防和治疗,提供新的靶点和方向。     

跨膜丝氨酸蛋白酶研究进展

跨膜丝氨酸蛋白酶(TMPRSSs),又名II型跨膜丝氨酸蛋白酶(TTSPs)是一类定位于细胞膜上具有保守丝氨酸蛋白酶结构域的蛋白家族,哺乳动物中已发现二十多个成员.TMPRSSs 基本结构类似,C端蛋白酶结构域在胞外,N端位于胞内,还拥有单跨膜结构域,差异之处在于主干区.TMPRSSs具有多种重要生理功能,功能异常可造成耳聋、癌症、贫血和高血压等多种疾病.本文对TMPRSSs基本特征、结构、生理功能及相关疾病进行综述.     

TMPRSS2重组蛋白阻断SARS-CoV-2假病毒的感染

为了探究Ⅱ型跨膜丝氨酸蛋白酶(type II transmembrane serine protease, TMPRSS2)重组蛋白阻断严重急性呼吸综合征冠状病毒2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)侵染宿主的能力,在体外构建假病毒感染细胞的体系,使用SARS-CoV-2 S (spike glycoprotein)蛋白携带水疱性口炎病毒(ΔG-VSV/荧光素酶)感染细胞,利用293F细胞体外纯化酶活及自身剪切位点突变的TMPRSS2重组蛋白,发现纯化的剪切位点R255Q和酶活位点S441A双突变的TMPRSS2重组蛋白,能够有效降低S蛋白与宿主细胞表面TMPRSS2的结合,进而阻断SARS-CoV-2假病毒对Calu3肺癌细胞系的感染。实验结果表明,使用突变的TMPRSS2重组蛋白竞争性结合病毒的刺突蛋白S,同抑制TMPRSS2蛋白酶的活性一样,都能阻断S蛋白的切割活化,抑制病毒与宿主细胞的膜融合,最终达到阻止病毒入侵的目的,这为阻断SARS-CoV-2感染提供了新的潜在靶点和思路。     

跨膜丝氨酸蛋白酶TMPRSS3与遗传性耳聋

跨膜丝氨酸蛋白酶TMPRSS3（transmembrane protease,serine 3）属于TTSPs（type Ⅱ transmembmne serine proteases）家族成员,在分子结构上,TMPRSS3具有典型的TTSPs结构域,如丝氨酸蛋白酶、LDLRA、SRCR等．TMPRSS3有不同的蛋白异构体,其中异构体A是体内最主要的存在形式,主要在内耳表达,亚细胞水平定位于内质网膜上,TMPRSS3基因缺陷是遗传性耳聋DFNB8／10的遗传基础,因此目前对TMPRSS3的功能研究主要集中在听觉系统方面,此外蛋白异构体D还可能是卵巢癌的生物学标志物．TMPRSS3是迄今为止发现的第一个基因突变能引起耳聋的蛋白酶,表明听觉通路上的某些关键调控因子可能作为它的生理学底物被水解激活,从而介导相应的信号转导途径,但它激活了哪些信号通道,目前尚不清楚．借鉴mCAP（mouse channel activating protease）的功能预测ENaC（epithelial sodium channel）可能是TMPRSS3的作用底物,推测TMPRSS3参与内耳Na^＋平衡调控,但仍有待于体内实验证实、当前酶学领域研究技术的革新发展,尤其酶降解组学的应用,为认识蛋白酶TMPRSS3的功能及其复杂的分子调控机制提供了新的捷径．     

呼吸道蛋白酶TMPRSS2和HAT裂解流感病毒血凝素的亚细胞定位及对蛋白酶抑制剂的不同敏感性

流感病毒表面糖蛋白血凝素（HA）被宿主细胞蛋白酶裂解是病毒感染和扩散的关键。已有研究表明,人呼吸道胰蛋白酶样蛋白酶（HAT）和跨膜丝氨酸蛋白酶S1成员2（TMPRSS2）是人类呼吸道裂解HA的蛋白酶。     

跨膜丝氨酸蛋白酶2结构与功能的研究进展

跨膜丝氨酸蛋白酶2(transmembrane serine protease 2,TMPRSS2)在人类疾病方面起着关键的作用。其一,TMPRSS2在介导癌症,包括前列腺癌、肺癌和结直肠癌的发生、发展中具有促进作用;其二,TMPRSS2在介导病毒感染,包括流感病毒、冠状病毒和轮状病毒中具有刺激病毒粒子活化、增强感染等作用。鉴于TMPRSS2在生理和病理方面的重要作用,结合目前可查阅的相关研究成果,该文从结构、功能等方面对TMPRSS2的研究进展进行归纳与总结,这将对今后有关TMPRSS2的研究工作,包括以TMPRSS2作为靶点的新药、疫苗等的研发具有重要的参考意义。     

新型冠状病毒相关TMPRSS2蛋白结构特征和抗原表位分析

采用生物信息学方法分析预测新型冠状病毒(Severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)跨膜蛋白酶丝氨酸2(transmembrane protease serine 2,TMPRSS2)的理化特性、结构特征和抗原表位,为抗SARS-CoV-2药物研...     

脂肪组织在铁稳态调节中的作用以及肥胖的铁缺乏机制

机体铁稳态的维持对正常生理功能至关重要。铁调素和铁调素调节蛋白在维持铁稳态中发挥重要作用。近来,丝氨酸蛋白酶基质-2在铁稳态中的作用越来越受到重视。此外,肥胖与铁缺乏的发生密切相关。一方面,肥胖人群脂肪组织高水平分泌白介素-6(interleukin-6, IL-6)、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)以及瘦素等脂肪因子,这些脂肪因子能够调节铁调素和铁调素调节蛋白表达;另一方面,肥胖个体脂肪组织也可直接表达铁调素与铁调素调节蛋白。运动作为一种非侵入性干预手段在调节肥胖与铁缺乏中可能发挥重要作用。本文将对近年来文献进行整理,以期能够为铁稳态维持以及肥胖与铁缺乏的机制提供一些新的视角。     

6-Methylcryptoacetalide, 6-methyl-epicryptoacetalide and 6-methylcryptotanshinone from Salvia aegyptiaca

From the whole plant of Salvia aegyptiaca, 6-methylcryptoacetalide, 6-methyl-epicryptoacetalide and 6-methylcryptotanshinone have been isolated and characterized, mainly by spectroscopic means. In addition to these novel diterpenoids, the known compounds 3beta-hydroxy-olean-12-en-28-oic acid, 3beta-hydroxy-oleana-11,13(18)-dien-28-oic acid, sitosterol-3beta-glucoside, sitosterol, stigmasterol, 5-hydroxy-7,3',4'-trimethoxyflavone and 5, 6-dihydroxy-7,3',4'-trimethoxyflavone were isolated.     

Preparation of 6-deoxy-6-fluorocellulose

6-Deoxy-6-fluorocellulose was prepared from cellulose 2,3-diacetate (1) or cellulose 2,3-dibenzoate (2) in various solvents, and was characterized by ¹⁹F and ¹³C NMR measurements. The best product, having ds of 0.95 at C-6 and 0.04 at C-3, was prepared from cellulose 2,3-dibenzoate in nitrobenzene. Other combinations of starting material and solvent gave a lower (≈ 0.8) ds of fluorine at C-6 and higher (≈ 0.12) at C-2 or C-3. Substitution at C-2 was observed when the combination of 1 and 1,4-dioxane, or 2 and chloroform was used. The products substituted at C-2 by fluorine were relatively resistant to acid hydrolysis.     

New 6-butylamino-6-deoxycellulose and 6-deoxy-6-pyridiniumcellulose derivatives with highest regioselectivity and completeness of reaction

This paper investigates the nucleophilic substitution (S(N)) reactions of tosylcellulose with butylamine and pyridine, respectively. The S(N) reactions of tosylcellulose 1 (DS(Total) 2.02; DS(C-6) 1.0) with butylamine carried out at 25, 50, 75 and 100 degrees C in both dimethyl sulfoxide (DMSO) and pure butylamine showed that the regioselectivity of substitution at C-6 of cellulose is temperature dependent: the highest regioselectivity at C-6 can be reached at 25 and 50 degrees C; substitution at C-2 also occurred at 75 and 100 degrees C. The substitution speed in pure butylamine is greater than that in the presence of DMSO. A complete and regioselective substitution at C-6 with a DS of 1.0 was obtained under the conditions of 50 degrees C, 40 h in butylamine. The substitution reactions of 1 with pyridine carried out at 25, 50, 75 and 100 degrees C for 24h in DMSO did not occur. In contrast to this the S(N) reactions done in pure pyridine showed that a temperature- and steric-dependent, regioselective substitution took place at C-6 at temperatures from 25 to 145 degrees C. The highest regioselectivity and completeness at C-6 can be obtained at 100 degrees C for 90 h, whereas at 145 degrees C substitution also occurs at C-2. The results were proved by 1H NMR and 13C NMR spectroscopy.     

Facile synthesis of 6-amino-6-deoxycellulose

6-Amino-6-deoxycellulose (4) was synthesized from cellulose by three reaction steps, namely bromination at C-6, displacement of bromine by azide ion, and reduction of the azide group to amino group, in 67% overall yield. The 13C NMR spectrum of compound 4 supports the expected structure for 6-amino-6-deoxycellulose. The degree of substitution of compound 4 was 0.96.     

Syntheses of (+/-)-methyl 6'alpha-demethyl-6'alpha-cyanoabscisate and (+/-)-methyl 6'alpha-demethyl-6'alpha-methoxycarbonylabscisate

New abscisic acid analogs possessing a cyano or methoxycarbonyl group at the 6'alpha-position of methyl abscisate were synthesized by regioselective hydrocyanation. These compounds had weak activity in the rice second leaf sheath elongation test.     

Syntheses of stable isotope-labeled 6 beta-hydroxycortisol, 6 beta-hydroxycortisone,and 6 beta-hydroxytestosterone

A method is described for the preparation of two types of multi-labeled 6 beta-hydroxycortisol containing either five deuterium atoms at C-19 methyl and C-1 methylene or four 13C atoms at C-1, C-2, C-4, and C-19 in addition to the five deuterium atoms for use as analytical internal standards for gas chromatography-mass spectrometry (GC-MS). BMD derivatives of [1,1,19,19,19-2H(5)]cortisone and [1,2,4,19-13C(4),1,1,19,19,19-2H(5)]cortisone (cortisone-2H(5)-BMD and cortisone-13C(4),2H(5)-BMD) were first synthesized via indan synthon method starting from optical active 11-oxoindanylpropionic acid and labeled isopropenyl anion ([1,1,3,3,3-2H(5)]- or [1,3-13C(2),1,1,3,3,3-2H(5)]isopropenyl anion). The labeled isopropenyl anion was prepared from commercially available [1,1,1,3,3,3-2H(6)]- or [1,3-13C(2),1,1,1,3,3,3-2H(6)]acetone. Ultraviolet (UV) irradiated autoxidation at C-6 position of 3-ethyl-3,5-dienol ether derivatives of the labeled cortisone-BMDs gave 6 beta-hydroxy-[1,1,19,19,19-2H(5)]cortisone-BMD and 6 beta-hydroxy-[1,2,4,19-13C(4),1,1,19,19,19-2H(5)]cortisone-BMD, respectively, as a mixture of 6 beta- and 6 alpha-epimers in a ratio of 4:1. Separation of 6 beta- and 6 alpha-epimers by thin-layer chromatography (TLC) and subsequent hydrolysis of the BMD group at C-17 gave pure labeled 6 beta-hydroxycortisone. After protecting the keto group at C-3 of the labeled 6 beta-hydroxycortisone-BMD as semicarbazone, reduction of 11-keto group with NaBH(4) and subsequent removal of the C-3 and C-17 protecting groups gave 6beta-hydroxy-[1,1,19,19,19-2H(5)]cortisol (6 beta-hydroxycortisol-2H(5)) and 6 beta-hydroxy-[1,2,4,19-13C(4),1,1,19,19,19-2H(5)]cortisol (6 beta-hydroxycortisol-13C(4),2H(5)), respectively, as a mixture of 6 beta- and 6 alpha-epimers (6 beta:6 alpha=4.4:1). The isotopic compositions of 6 beta-hydroxycortisol-2H(5) and 6 beta-hydroxycortisol-13C(4),2H(5) were 90.9 and 92.1 at.%, respectively. Furthermore, 6 beta-hydroxy-[1 alpha,16,16,17 alpha-2H(4)]testosterone was synthesized by the UV irradiated autoxidation at C-6 position of 3-ethyl-3,5-dienol ether derivative of deuterium-labeled testosterone ([1 alpha,16,16,17 alpha-2H(4)]testosterone) obtained by using catalytic deuteration and hydrogen-deuterium exchange reactions.