脑血红素加氧酶系统的作用研究

血红素加氧酶（HO）是降解血红素的微粒体酶系统,催化降解血红素生成一氧化碳（CO）、胆绿素和铁离子,同工酶HO-1和HO-2广泛分布于脑中,具有不同的调控机制,可能发挥着调节NO水平,抗氧化应激,参与神经元退行性变等重要作用。     

植物血红素加氧酶生理功能研究进展(综述)

血红素加氧酶（heme oxygenase, HO）是血红素分解代谢的关键酶类,在植物体内起着重要的作用。本文从HO在植物光敏色素合成中的作用、对植物根形态建成、提高植物抗胁迫反应能力、促进植物种子萌发和调节植物气孔关闭等方面,综述植物HO生理功能的最新研究进展,并对HO未来研究方向进行展望。     

植物血红素加氧酶研究进展

本文综述了血红素加氧酶（HO）的催化机理、结构特征、遗传学突变体以及在光敏色素发色团合成、调控根形态发生和参与植物对非生物胁迫应答中的作用及信号转导。同时,介绍了紫外线和盐胁迫等逆境条件以及生长素和脱落酸等植物激素对HO基因表达调控等方面的研究进展。     

血红素加氧酶系的共固定化及部分性质研究

为了检测血红素加氧酶系分子间的相互作用和共固定化酶系的反应动力学,利用２′,５′－ＡＤＰ－Ｓｅｐｈａｒｏｓｅ４Ｂ柱对血红素加氧酶、ＮＡＤＰＨ－细胞色素ｃ还原酶和胆绿素还原酶进行非膜重组,再以纤维素为载体,用重氮化法固定此重组的酶复合物和共固定非重组的３种酶,发现固定化的重组酶系比非重组酶系能更好地发挥协同作用,在室温条件下可催化血红素一步合成胆红素．共固定化酶的最适ｐＨ为７．２,最适温度为３８℃,Ｋｍ值为０．９３μｍｏｌ／Ｌ．巯基试剂和金属卟淋对固定化酶有抑制作用,共固定化酶比游离酶系稳定性提高,３８℃下的操作半寿期可延长至４２０ｈ,在０～４℃保存两个月其酶活力无明显变化．     

血红素加氧酶介导GA对小麦糊粉层中α-淀粉酶的诱导表达

单独以赤霉素（GA）处理或与HO．1诱导物高铁血红素（Ht）和CO水溶液组合处理均导致小麦糊粉层中血红素加氧酶（H0）活性的提高,同时仪-淀粉酶基因表达和α-淀粉酶活性也明显受诱导;用HO-1专一性抑制剂锌原卟啉（ZnPPIX）预处理6h后,上述效应部分受阻断。这暗示HO可能参与GA诱导的α-淀粉酶基因表达。     

人血红素加氧酶同工酶的分离纯化初报

首次报道了人肝脏血红素加氧酶的同工酶的分离纯化,并初步探讨了它们的性质,采用ＤＥＡＥ－ＳｅｐｈａｄｅｘＡ－２５和羟基磷灰石柱层析法从人肝脏分离纯化ＨＯ的同工酶,酶活性检测、ＳＤＳ－ＰＡＧＥ分析结果显示,人肝脏微粒体含量ＨＯ的同工酶,按洗脱先后顺序分别得到分子量为３００００和３６０００的ＨＯ－１和ＨＯ－２．酶促反应中需相同辅酶参与,其中酶活性ＨＯ－１明显高于ＨＯ－２,两之比为２．４：１,从分子量和     

人体血红素加氧酶-1的研究进展

血红素加氧酶（heme oxygenase,HO)是哺乳动物中血红素代谢的限速酶,HO－1是HO同功酶之一,主要分布在肝、脾、肺等多种脏器,具有调节和保护功能。作者拟从人体HO－1蛋白的晶体结构、HO－1的功能和HO－1表达的诱导因素,以及HO－1基因的表达与调控等研究进展做一综述。     

血红素加氧酶同工酶的结构与功能

血红素加氧酶(Hemeoxygenase,HO)是一种膜结合蛋白,哺乳动物体内共发现3种同工酶,HO 1、HO 2和HO 3.HO能催化血红素降解生成α 胆绿素,铁离子和CO.这些产物都有着重要的生理作用.对HO的结构和功能研究有助于人们正确认识其催化机理和生理意义.因此从HO的催化作用、HO同工酶、HO同工酶的活性部位及HO催化的区域选择性方面作一综述.     

内源性一氧化碳在大鼠败血症休克时低血压发生机制中的作用

A sepsis model induced by cecal ligation and puncture was used to study the role of endogenous carbon monoxide in hypotension pathogenesis of rats during septic shock. After administration of zinc deuteroporphyrin 2,4-bisglycol (ZnDPBG),an inhibitor of heme oxygenase (HO),blood pressure (BP),HO activity and carbon monoxide (CO) release from vascular muscle tissue were measured. The results showed that BP of sepsis rats, including systolic and diastolic arterial BP, decreased significantly while HO activity and CO content were significantly increased. In contrast, after administration of ZnDPBG, BP of sepsis rats was significantly increased while the HO activity and CO production were significantly decreased. These findings suggest that HO activity and CO release within vascular musculature are increased during septic shock; inhibition of HO may elevate BP of rats during septic shock through a decrease of endogenous CO production. It is concluded that endogenous CO derived from vascular muscle cells plays an important role in regulating vascular tone, and the up-regulation of HO activity followed by subsequent CO production contributes to hypotension pathogenesis during septic shock.     

Time-resolved Studies of IsdG Protein Identify Molecular Signposts along the Non-canonical Heme Oxygenase Pathway

IsdGs are heme monooxygenases that break open the tetrapyrrole, releasing the iron, and thereby allowing bacteria expressing this protein to use heme as a nutritional iron source. Little is currently known about the mechanism by which IsdGs degrade heme, although the products differ from those generated by canonical heme oxygenases. A synthesis of time-resolved techniques, including in proteo mass spectrometry and conventional and stopped-flow UV/visible spectroscopy, was used in conjunction with analytical methods to define the reaction steps mediated by IsdG from Staphylococcus aureus and their time scales. An apparent meso-hydroxyheme (forming with k = 0.6 min⁻¹, pH 7.4, 10 mm ascorbate, 10 μm IsdG-heme, 22 °C) was identified as a likely common intermediate with the canonical heme oxygenases. Unlike heme oxygenases, this intermediate does not form with added H₂O₂ nor does it convert to verdoheme and CO. Rather, the next observable intermediates (k = 0.16 min⁻¹) were a set of formyloxobilin isomers, similar to the mycobilin products of the IsdG homolog from Mycobacterium tuberculosis (MhuD). These converted in separate fast and slow phases to β-/δ-staphylobilin isomers and formaldehyde (CH₂O). Controlled release of this unusual C1 product may support IsdG''s dual role as both an oxygenase and a sensor of heme availability in S. aureus.     

Heme oxygenase/carbon monoxide signaling pathways: Regulation and functional significance

Carbon monoxide (CO), a gaseous second messenger, arises in biological systems during the oxidative catabolism of heme by the heme oxygenase (HO) enzymes. HO exists as constitutive (HO-2, HO-3) and inducible isoforms (HO-1), the latter which responds to regulation by multiple stress-stimuli. HO-1 confers protection in vitro and in vivo against oxidative cellular stress. Although the redox active compounds that are generated from HO activity (i.e. iron, biliverdin-IX, and bilirubin-IX) potentially modulate oxidative stress resistance, increasing evidence points to cytoprotective roles for CO. Though not reactive, CO regulates vascular processes such as vessel tone, smooth muscle proliferation, and platelet aggregation, and possibly functions as a neurotransmitter. The latter effects of CO depend on the activation of guanylate cyclase activity by direct binding to the heme moiety of the enzyme, stimulating the production of cyclic 3:5-guanosine monophosphate. CO potentially interacts with other intracellular hemoprotein targets, though little is known about the functional significance of such interactions. Recent progress indicates that CO exerts novel anti-inflammatory and anti-apoptotic effects dependent on the modulation of the p38 mitogen activated protein kinase (MAPK)-signaling pathway. By virtue of these effects, CO confers protection in oxidative lung injury models, and likely plays a role in HO-1 mediated tissue protection.     

Heme oxygenase-1 derived carbon monoxide permits maturation of myeloid cells

Critical functions of the immune system are maintained by the ability of myeloid progenitors to differentiate and mature into macrophages. We hypothesized that the cytoprotective gas molecule carbon monoxide (CO), generated endogenously by heme oxygenases (HO), promotes differentiation of progenitors into functional macrophages. Deletion of HO-1, specifically in the myeloid lineage (Lyz-Cre:Hmox1^flfl), attenuated the ability of myeloid progenitors to differentiate toward macrophages and decreased the expression of macrophage markers, CD14 and macrophage colony-stimulating factor receptor (MCSFR). We showed that HO-1 and CO induced CD14 expression and efficiently increased expansion and differentiation of myeloid cells into macrophages. Further, CO sensitized myeloid cells to treatment with MCSF at low doses by increasing MCSFR expression, mediated partially through a PI3K-Akt-dependent mechanism. Exposure of mice to CO in a model of marginal bone marrow transplantation significantly improved donor myeloid cell engraftment efficiency, expansion and differentiation, which corresponded to increased serum levels of GM-CSF, IL-1α and MCP-1. Collectively, we conclude that HO-1 and CO in part are critical for myeloid cell differentiation. CO may prove to be a novel therapeutic agent to improve functional recovery of bone marrow cells in patients undergoing irradiation, chemotherapy and/or bone marrow transplantation.     

血红素氧合酶HugZ组氨酸-249对组氨酸-245侧链缺失补偿的结构基础

血红素氧合酶HugZ是幽门螺旋杆菌(Helicobacter pylori)利用宿主血红素作为铁源的关键蛋白．HugZ的His245残基侧链咪唑基与血红素中心铁配位结合,是酶活中心的重要组成部分．用定点突变的方法构建HugZ突变体H245A、H249A和H245A/H249A基因,并将突变体蛋白表达纯化．通过X射线晶体学途径解析了突变体H245A与血红素复合物的2.55Å分辨率晶体结构．结构解析表明,HugZ的His249残基侧链咪唑基团与血红素的铁原子结合,从而补偿了His245侧链缺失．这种结构特征在已知血红素氧合酶中未曾发现．Val238 ψ平面的可翻转和Gly239的柔性是His249能与血红素配位结合的关键原因,二者的共同作用改变了C端肽链的走向,使Val238与His249之间的柔性回折与α1螺旋的相互作用发生解离,并向远离血红素的方向伸展．HugZ蛋白与血红素结合的光谱实验证明HugZ柔性C端上的组氨酸残基有利于HugZ与血红素的结合．研究结果表明,含多个组氨酸残基柔性C端的存在有利于血红素氧合酶HugZ结合和分解血红素．     

革兰氏阴性菌血红素转运系统结构及功能特点

铁是大多数生物包括细菌生存的必需营养元素．对于感染宿主的致病细菌,血红素(heme/haem)可作为一种主要的铁来源．血红素转运系统在革兰氏阴性菌和革兰氏阳性菌中均有发现和鉴定,其转运机制在革兰氏阴性菌中有较为深入研究．革兰氏阴性菌血红素转运系统主要由分泌于细胞外的血红素载体(hemophore)、血红素受体、TonB ExbB ExbD复合物、ABC转运体、血红素降解蛋白和调控蛋白等结构单元组成．对参与该系统的各个蛋白结构特点以及它们之间的相互作用机制的讨论,有助于对病原菌致病机制的深入研究和抗菌新药的研发．     

大鼠肝及脑组织中微粒体血红素加氧酶同工酶研究

采用离子交换层析和免疫印迹法分离、纯化和分析血红素和苯肼诱导后大鼠肝脏、脑组织.结果显示：纯化诱导后的大鼠肝脏,获得 HO-1和 HO-2,前者活性高于后者为2∶1.未诱导的大鼠肝脏仅获得HO-2,但诱导剂作用后,HO-1活性明显增加,而HO-2未见改变.HO-1和HO-2表观分子质量分别为30 ku和36 ku.诱导剂未作用的肝脏及作用的脑层析后仅获得HO-2活性的洗脱峰.免疫印迹法检测发现大鼠肝脏HO-2抗体与脑HO-2间有交叉反应,与肝脏HO-1无反应.实验表明在诱导剂作用的大鼠肝脏内含HO-1和HO-2同工酶,其中HO-1为诱导型酶.诱导剂作用的脑仅含HO-2.两种构型在表观分子质量,诱导性和免疫化学特性方面明显不同.     

Expression of Heme Oxygenase Isozyme mRNAs in the Human Brain and Induction of Heme Oxygenase-1 by Nitric Oxide Donors

Abstract: Heme oxygenase is an essential enzyme in the heme catabolism that produces carbon monoxide (CO). This study was designed to examine the expression of two heme oxygenase isozyme mRNAs in the human brain and to explore the involvement of nitric oxide (NO) and various neuropeptides in the regulation of their expression. Northern blot analysis showed the expression of heme oxygenase-1 and heme oxygenase-2 mRNAs in every region of the brain examined, with the highest levels found in the frontal cortex, temporal cortex, occipital cortex, and hypothalamus. In a human glioblastoma cell line, T98G, treatment with any of three types of NO donors—sodium nitroprusside, 3-morpholinosydnonimine, and S -nitroso- l -glutathione—caused a significant increase in the levels of heme oxygenase-1 mRNA but not in the levels of heme oxygenase-2 and heat-shock protein 70 mRNAs. Sodium nitroprusside increased the levels of heme oxygenase-1 protein but not the levels of heat-shock protein 70 in T98G cells. The increase in content of heme oxygenase-1 mRNA caused by sodium nitroprusside was completely abolished by the treatment with actinomycin D. On the other hand, the levels of heme oxygenase isozyme mRNAs were not noticeably changed in T98G cells following the treatment with 8-bromo cyclic GMP, sodium nitrite, or various neuropeptides, such as calcitonin gene-related peptide, endothelin-1, and corticotropin-releasing hormone. The present study has shown the expression profiles of heme oxygenase-1 and -2 mRNAs in the human brain and the induction of heme oxygenase-1 mRNA caused by NO donors in T98G cells. These findings raise a possibility that the CO/heme oxygenase system may function in concert with the NO/NO synthase system in the brain.