多ADP-核糖聚合酶家族

分离鉴定多功能的核基质蛋白及核基质结合蛋白是目前核基质研究的一个重要领域。通过与转录因子、核基质结合元件以及DNA间相互作用,核基质结合蛋白在DNA复制、转录、加工修饰等细胞内事件中起着支持和调节的作用。多ADP-核糖聚合酶[poly(ADP—ribose)polymerase,PARP]是一种高度保守的核基质结合蛋白,在多种活动例如基因组损伤修复、细胞凋亡、信号转导、基因表达调控中都发挥着调节的功能。PARP的潜在生物学功能已越来越引起国内外研究人员的关注。     

多聚ADP-核糖聚合酶与帕金森病

多聚ADP-核糖聚合酶(PARP)可以被DNA损伤断裂激活,使多种核蛋白发生聚ADP核糖化,促DNA的修复。然而,若PARP过度活化则将耗竭细胞内NAD 和能量而导致细胞凋亡和坏死。PARP的过度活化是帕金森病发病的重要危险因素,开发PARP抑制剂,将为临床治疗帕金森病提供新的希望。     

蛋白激酶D:一个新的蛋白激酶家族

蛋白激酶D属丝/苏氨酸蛋白激酶家族,主要包括3个家族成员,结构相对保守,参与细胞增殖与分化、细胞凋亡、免疫反应等多种细胞生理和病理过程.该文介绍该家族成员的结构、功能及其在疾病治疗过程中作为治疗靶位的潜力.     

抗菌药物治疗疾病的新靶位——丙氨酸消旋酶

丙氨酸消旋酶是以磷酸吡哆醛为辅酶,催化L-丙氨酸与D-丙氨酸相互转化的一种酶,它广泛分布在低等生物,而不存在于人类等高等真核生物中.来自不同物种的丙氨酸消旋酶一级结构同源性较高,其大多功能单位为同源二聚体,拥有2个相同的活性中心,每个活性中心均是由来自不同亚基的2个保守残基共同组成.丙氨酸消旋酶催化生成的产物D-丙氨酸是合成细菌细胞壁肽聚糖的重要成分,也是调节细菌孢子萌芽的关键因子.因而丙氨酸消旋酶与由细菌引起的肺结核、炭疽热、中耳炎等疾病密切相关.近年来丙氨酸消旋酶已成为设计抗菌药物的又一理想靶位.本文从丙氨酸消旋酶的结构、功能、作用机理、抑制剂以及其与疾病的关系等方面进行了阐述.     

IL-13在支气管哮喘中的作用机制及治疗靶位

支气管哮喘是由多种细胞包括气道炎性细胞、结构细胞和多种细胞组分参与的气道慢性炎症性疾病。其发病原因复杂,以反复发作的呼吸困难、气道的高反应性和慢性炎症为特点。细胞因子作为免疫活性细胞中的效应分子,具有的免疫调节作用,诸多学者认为白介素-13(interleukin-13,IL-13)在哮喘发病中扮演重要角色,其拮抗剂有望成为哮喘治疗的新方法,本文欲将IL-13的生物学功能、IL-13在支气管哮喘中的作用机制及干预治疗靶位加以综述,为制定哮喘防治策略、开发新治疗技术提供新思路。     

抑制聚ADP-核糖聚合酶-1活性降低HEK293/tau441细胞tau蛋白的磷酸化

为了研究聚ADP-核糖聚合酶-1 fpoly(ADP-ribose)polymerase-1,PARP-1]对微管相关蛋白tau磷酸化水平的影响,本实验分别用不同剂量(0.5,1,2,4 mmol/L)的PARP-1的抑制剂3-氨基苯甲酰胺(3-aminobenzamide,3-AB)处理稳定表达tau441蛋白的HE...     

肠道病毒71型基因组中小干扰RNA的靶位点预测

肠道病毒71型（EV71）已经在世界范围内有过十多次大的爆发与流行,近年来EV71病毒的流行在亚洲逐渐呈上升的趋势,但是目前尚无有效的治疗措施,因此迫切需要一种治疗EV71的有效药物。本文采用生物信息学的方法,对人类EV71病毒三个不同株型（SHZH03,SHZH98和MS）RNA序列的局域二级结构进行了预测,并从这些病毒株的基因组中分别得到了长度在21～25nt的小干扰RNA靶序列碱基片段。这一结果将有助于治疗EV71药物的开发研究,对预防和控制EV71的爆发和流行也会有重要意义。     

幽门螺杆菌感染治疗的新靶位

抗生素治疗幽门螺杆菌感染面临着细菌耐药性的威胁,研究该细菌未知基因的功能,寻找新的抗菌靶,将为预防和治疗幽门螺杆菌感染开辟新途径。将机体适应性免疫应答运用于幽门螺杆菌感染的治疗,亦有广阔前景。     

聚ADP核糖聚合酶的结构及基因表达和调控

聚ＡＤＰ核糖基化反应是在细胞内聚ＡＤＰ核糖聚合酶（ＰＡＲＰ）的催化下,以ＮＡＤ为底物,将聚ＡＤＰ核糖多聚体共价连接到接受体蛋白上去的过程．这种蛋白质的转译后修饰形式参与细胞内很多重要的生物事件．本文对催化聚ＡＤＰ核糖基化反应的ＰＡＲＰ酶的结构特性、编码ＰＡＲＰ基因的表达与调控,以及ＰＡＲＰ酶对细胞内其它基因表达的影响进行了综述。     

Poly(ADP-ribose): PARadigms and PARadoxes

Poly(ADP-ribosyl)ation (PARylation) is a posttranslational protein modification (PTM) catalyzed by members of the poly(ADP-ribose) polymerase (PARP) enzyme family. PARPs use NAD⁺ as substrate and upon cleaving off nicotinamide they transfer the ADP-ribosyl moiety covalently to suitable acceptor proteins and elongate the chain by adding further ADP-ribose units to create a branched polymer, termed poly(ADP-ribose) (PAR), which is rapidly degraded by poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3). In recent years several key discoveries changed the way we look at the biological roles and mode of operation of PARylation. These paradigm shifts include but are not limited to (1) a single PARP enzyme expanding to a PARP family; (2) DNA-break dependent activation extended to several other DNA dependent and independent PARP-activation mechanisms; (3) one molecular mechanism (covalent PARylation of target proteins) underlying the biological effect of PARPs is now complemented by several other mechanisms such as protein–protein interactions, PAR signaling, modulation of NAD⁺ pools and (4) one principal biological role in DNA damage sensing expanded to numerous, diverse biological functions identifying PARP-1 as a real moonlighting protein. Here we review the most important paradigm shifts in PARylation research and also highlight some of the many controversial issues (or paradoxes) of the field such as (1) the mostly synergistic and not antagonistic biological effects of PARP-1 and PARG; (2) mitochondrial PARylation and PAR decomposition, (3) the cross-talk between PARylation and signaling pathways (protein kinases, phosphatases, calcium) and the (4) divergent roles of PARP/PARylation in longevity and in age-related diseases.     

Poly(etheno ADP-ribose) blocks poly(ADP-ribose) glycohydrolase activity

Poly(ADP-ribose) is a biopolymer synthesized by poly(ADP-ribose) polymerases. Recent findings suggest the possibility for modulation of cellular functions including cell death and mitosis by poly(ADP-ribose). Derivatization of poly(ADP-ribose) may be useful for investigating the effects of poly(ADP-ribose) on various cellular processes. We prepared poly(etheno ADP-ribose) (poly(epsilonADP-ribose)) by converting the adenine moiety of poly(ADP-ribose) to 1-N(6)-etheno adenine residues. Poly(epsilonADP-ribose) is shown to be highly resistant to digestion by poly(ADP-ribose) glycohydrolase (Parg). On the other hand, poly(epsilonADP-ribose) could be readily digested by phosphodiesterase. Furthermore, poly(epsilonADP-ribose) inhibited Parg activity to hydrolyse ribose-ribose bonds of poly(ADP-ribose). This study suggests the possibility that poly(epsilonADP-ribose) might be a useful tool for studying the poly(ADP-ribose) dynamics and function of Parg. This study also implies that modification of the adenine moiety of poly(ADP-ribose) abrogates the susceptibility to digestion by Parg.     

Poly(ADP-ribose) Polymerase (PARP-1) in Homologous Recombination and as a Target for Cancer Therapy

Poly(ADP-ribose) polymerase (PARP-1) binds to DNA breaks to facilitate DNA repair. However, the role of PARP-1 in DNA repair appears to not be critical since PARP-1 knockout mice are viable, fertile and do not develop early onset tumours. Cells isolated from these mice show an increased level of homologous recombination. There is an intricate link between homologous recombination and PARP-1 and a possible role for PARP-1 in DNA double-strand break repair. Although PARP-1 appears not to be required for homologous recombination itself, it regulates the process through its involvement in the repair of DNA single-strand breaks (SSBs). SSBs persisting into the S phase of the cell cycle collapse replication forks, triggering homologous recombination for replication restart. We discuss the recent discoveries on the use of PARP-1 inhibitors as a targeted cancer therapy for recombination deficient cancers, such as BRCA2 tumours.     

Poly(ADP-ribose)polymerase: a novel finger protein.

By Energy Dispersive X-ray fluorescence we have determined that calf thymus poly(ADP-ribose) polymerase binds two zinc ions per enzyme molecule. Using 65Zn (II) for detection of zinc binding proteins and polypeptides on western blots, we found that the zinc binding sites are localized in a 29 kd N-terminal fragment which is included in the DNA binding domain. Metal depletion and restoration experiments proved that zinc is essential for the binding of this fragment to DNA as tested by Southwestern assay. These results correlate with the existence of two putative zinc finger motifs present in the N-terminal part of the human enzyme. Poly(ADP-ribose)polymerase fingers could be involved in the recognition of DNA strand breaks and therefore in enzyme activation.     

Poly(ADP-ribose) makes a date with death

Poly(ADP-ribose) polymerase (PARP) enzymes catalyze the conversion of NAD(+) to polymers of poly(ADP-ribose) (PAR). Although its role in the DNA-damage response has long been recognized, recent work indicates that PAR itself acts at the mitochondria to directly induce cell death through stimulation of apoptosis-inducing factor (AIF) release. This review discusses PAR synthesis and degradation, and the role of PAR misregulation in various disease states. Attention is given to opportunities for therapeutic intervention with small molecules that are involved in PAR signaling, with specific focus on poly(ADP-ribose) glycohydrolase (PARG) and AIF.     

2,5-Diketopiperazines: A New Class of Poly(ADP-ribose)polymerase Inhibitors

We show for the first time that natural 2,5-diketopiperazines (cyclic dipeptides) can suppress the activity of the important anticancer target poly(ADP-ribose)polymerase (PARP). Cyclo(L-Ala-L-Ala) and cyclo(L-Ala-D-Ala) can interact with the key residues of the PARP-1 active site, as demonstrated using docking and molecular dynamics simulations. One of the amide groups of cyclo(L-Ala-L-Ala) and cyclo(L-Ala-D-Ala) forms hydrogen bonds with the Gly863 residue, while the second amide group can form a hydrogen bond with the catalytic residue Glu988, and the side chain can make a hydrophobic contact with Ala898. Newly identified diketopiperazine inhibitors are promising basic structures for the design of more effective inhibitors of PARP family enzymes. The piperazine core with two chiral centers provides many opportunities for structural optimization.