Nat Commun:与黄疸病有关的抗氧化酶的突破性进展

2021-06-09 Viho MedSci原创

黄疸,以皮肤变黄为标志,在婴儿中很常见,但也是各种成人疾病的症状。这种变色是由过量的胆红素(BR)引起的,胆红素是使胆汁呈现黄色的物质。

黄疸,以皮肤变黄为标志,在婴儿中很常见,但也是各种成人疾病的症状。这种变色是由过量的胆红素(BR)引起的,胆红素是使胆汁呈现黄色的物质。然而,胆红素也是一种重要的抗氧化剂,在健康水平下保护细胞免受过氧化物的损害。不过,它在体内的产生长期以来一直是一个不确定的来源。

最近在Nature Communications杂志上报道,研究人员发现胆红素还原酶如何产生胆红素,导致胆汁的黄色和黄疸的皮肤。胆绿素还原酶(BVR),最早发现于20世纪60年代,是将胆绿素IXα(haem降解产物)转化为胆红素IXα(BR)的酶;该产物是一种胆汁色素,是黄疸的来源。该酶包裹着BV,并转移两个氢原子--一个正极和一个负极--以产生黄色的抗氧化剂。然而,生物学家无法确定该酶的哪一部分在化学上参与了这一过程(活性部位),或正氢来自何处。

以前的研究使用的是来自老鼠的BVR,没有能够很好地将这种酶结晶,以确定它是如何与BV结合的。科学家们意识到,塞纳氏菌中的相同酶具有几乎相同的折叠形状,但更容易通过X射线晶体学进行检查"。

研究人员在活性部位发现了两个BV分子--一个堆叠在另一个上,尽管只有一个被转化为BR。从X射线数据中,他们推断出为什么需要两个。第一个BV,由于它接受负氢的方向,不能直接从酶中接受正氢。相反,第二个BV作为一个氢气管道来实现这一过程,但它本身并没有转化为BR。

BVR催化的反应

胆绿素还原酶催化HAEM降解的最后一步,以NAD(P)H为辅助因子,还原胆绿素生成主要的亲脂抗氧化剂胆红素。

BVR底物-辅因子-酶三元配合物的结构,揭示了两个胆绿素分子在活性位上与堆积几何结合的结合模式。这种结构和直接突变的结果可以解释BVR如何将Bv降低到Br,从而解决了关于BVR反应机制的一个长期的谜团。指定的两个胆绿素分子,即近端和远端胆绿素,在活性部位与堆积的几何结构结合。NADP的烟酰胺环+位于靠近近端胆绿素的反应部位,支持氢化物直接攻击近端胆绿素的位置。

根据该结构,研究人员提出了该酶的328个氨基酸中哪一个实际上提供了正氢原子。然后,他们进行了实验,对酶进行了突变,以专门去除该氨基酸,同时保留其他的氨基酸不动。由此产生的酶,无论是来自细菌、大鼠还是人类,都几乎无法产生BR。进一步的实验证实,大鼠和人类的酶也使用两个BV分子,就像细菌一样。

通过对BVR反应的结构和机制的理解,可以开发出针对严重黄疸的新抑制剂。在酶的过程中,两个底物分子如此整齐的堆叠是非常罕见的。了解BR的产生不仅对生物化学来说是令人兴奋的,而且应该帮助我们开发治疗因BR过剩导致的严重黄疸为标志的疾病的药物。

文章参考:Haruna Takao, Kei Hirabayashi, Yuki Nishigaya, Haruna Kouriki, Tetsuko Nakaniwa, Yoshinori Hagiwara, Jiro Harada, Hideaki Sato, Toshimasa Yamazaki, Yoichi Sakakibara, Masahito Suiko, Yujiro Asada, Yasuhiro Takahashi, Ken Yamamoto, Keiichi Fukuyama, Masakazu Sugishima, Kei Wada. A substrate-bound structure of cyanobacterial biliverdin reductase identifies stacked substrates as critical for activityNature Communications, 2017; 8: 14397 DOI: 10.1038/ncomms14397

版权声明:
本网站所有内容来源注明为“梅斯医学”或“MedSci原创”的文字、图片和音视频资料,版权均属于梅斯医学所有。非经授权,任何媒体、网站或个人不得转载,授权转载时须注明来源为“梅斯医学”。其它来源的文章系转载文章,或“梅斯号”自媒体发布的文章,仅系出于传递更多信息之目的,本站仅负责审核内容合规,其内容不代表本站立场,本站不负责内容的准确性和版权。如果存在侵权、或不希望被转载的媒体或个人可与我们联系,我们将立即进行删除处理。
在此留言
评论区 (5)
#插入话题
  1. [GetPortalCommentsPageByObjectIdResponse(id=1885220, encodeId=c8a51885220a5, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Jan 28 19:40:42 CST 2022, time=2022-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2088022, encodeId=0c06208802242, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Sun Apr 24 15:40:42 CST 2022, time=2022-04-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972871, encodeId=c0c69e28716b, content=加油💪, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d9665485729, createdName=ms5000001756152328, createdTime=Fri Jun 11 15:27:46 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1422831, encodeId=22de1422831b9, content=<a href='/topic/show?id=b2361031e6fc' target=_blank style='color:#2F92EE;'>#黄疸#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103176, encryptionId=b2361031e6fc, topicName=黄疸)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=28ad3737144, createdName=楚秀娟, createdTime=Fri Jun 11 14:40:42 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972424, encodeId=cfa49e242479, content=谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20221103/2796e00c9b4549e3b313ed9e7accc68f/b52d6d98bbe04782b5a4e2dd1ee80be2.jpeg, createdBy=078e1614372, createdName=MedSciZeng, createdTime=Thu Jun 10 10:16:36 CST 2021, time=2021-06-10, status=1, ipAttribution=)]
    2022-01-28 liye789132251
  2. [GetPortalCommentsPageByObjectIdResponse(id=1885220, encodeId=c8a51885220a5, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Jan 28 19:40:42 CST 2022, time=2022-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2088022, encodeId=0c06208802242, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Sun Apr 24 15:40:42 CST 2022, time=2022-04-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972871, encodeId=c0c69e28716b, content=加油💪, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d9665485729, createdName=ms5000001756152328, createdTime=Fri Jun 11 15:27:46 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1422831, encodeId=22de1422831b9, content=<a href='/topic/show?id=b2361031e6fc' target=_blank style='color:#2F92EE;'>#黄疸#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103176, encryptionId=b2361031e6fc, topicName=黄疸)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=28ad3737144, createdName=楚秀娟, createdTime=Fri Jun 11 14:40:42 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972424, encodeId=cfa49e242479, content=谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20221103/2796e00c9b4549e3b313ed9e7accc68f/b52d6d98bbe04782b5a4e2dd1ee80be2.jpeg, createdBy=078e1614372, createdName=MedSciZeng, createdTime=Thu Jun 10 10:16:36 CST 2021, time=2021-06-10, status=1, ipAttribution=)]
    2022-04-24 liuli5079
  3. [GetPortalCommentsPageByObjectIdResponse(id=1885220, encodeId=c8a51885220a5, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Jan 28 19:40:42 CST 2022, time=2022-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2088022, encodeId=0c06208802242, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Sun Apr 24 15:40:42 CST 2022, time=2022-04-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972871, encodeId=c0c69e28716b, content=加油💪, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d9665485729, createdName=ms5000001756152328, createdTime=Fri Jun 11 15:27:46 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1422831, encodeId=22de1422831b9, content=<a href='/topic/show?id=b2361031e6fc' target=_blank style='color:#2F92EE;'>#黄疸#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103176, encryptionId=b2361031e6fc, topicName=黄疸)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=28ad3737144, createdName=楚秀娟, createdTime=Fri Jun 11 14:40:42 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972424, encodeId=cfa49e242479, content=谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20221103/2796e00c9b4549e3b313ed9e7accc68f/b52d6d98bbe04782b5a4e2dd1ee80be2.jpeg, createdBy=078e1614372, createdName=MedSciZeng, createdTime=Thu Jun 10 10:16:36 CST 2021, time=2021-06-10, status=1, ipAttribution=)]
    2021-06-11 ms5000001756152328

    加油💪

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1885220, encodeId=c8a51885220a5, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Jan 28 19:40:42 CST 2022, time=2022-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2088022, encodeId=0c06208802242, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Sun Apr 24 15:40:42 CST 2022, time=2022-04-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972871, encodeId=c0c69e28716b, content=加油💪, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d9665485729, createdName=ms5000001756152328, createdTime=Fri Jun 11 15:27:46 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1422831, encodeId=22de1422831b9, content=<a href='/topic/show?id=b2361031e6fc' target=_blank style='color:#2F92EE;'>#黄疸#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103176, encryptionId=b2361031e6fc, topicName=黄疸)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=28ad3737144, createdName=楚秀娟, createdTime=Fri Jun 11 14:40:42 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972424, encodeId=cfa49e242479, content=谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20221103/2796e00c9b4549e3b313ed9e7accc68f/b52d6d98bbe04782b5a4e2dd1ee80be2.jpeg, createdBy=078e1614372, createdName=MedSciZeng, createdTime=Thu Jun 10 10:16:36 CST 2021, time=2021-06-10, status=1, ipAttribution=)]
    2021-06-11 楚秀娟
  5. [GetPortalCommentsPageByObjectIdResponse(id=1885220, encodeId=c8a51885220a5, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Jan 28 19:40:42 CST 2022, time=2022-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2088022, encodeId=0c06208802242, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Sun Apr 24 15:40:42 CST 2022, time=2022-04-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972871, encodeId=c0c69e28716b, content=加油💪, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d9665485729, createdName=ms5000001756152328, createdTime=Fri Jun 11 15:27:46 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1422831, encodeId=22de1422831b9, content=<a href='/topic/show?id=b2361031e6fc' target=_blank style='color:#2F92EE;'>#黄疸#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103176, encryptionId=b2361031e6fc, topicName=黄疸)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=28ad3737144, createdName=楚秀娟, createdTime=Fri Jun 11 14:40:42 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972424, encodeId=cfa49e242479, content=谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20221103/2796e00c9b4549e3b313ed9e7accc68f/b52d6d98bbe04782b5a4e2dd1ee80be2.jpeg, createdBy=078e1614372, createdName=MedSciZeng, createdTime=Thu Jun 10 10:16:36 CST 2021, time=2021-06-10, status=1, ipAttribution=)]
    2021-06-10 MedSciZeng

    谢谢

    0

相关资讯

NEJM:肝内胆管扩张-病例报道

考虑到许多考虑因素,包括肝动脉和门静脉均已受累,医务人员认为该肿瘤不可切除。除胆道引流外,该患者只进行了支持性姑息治疗。

JAMA Surg:导管内乳头粘液性肿瘤积极监测过程中与恶性病变相关的动态因素研究

导管内乳头粘液性肿瘤患者积极监测过程中,基线存在高危特征以及随访过程中出现新需关注特征患者的恶性进展风险较高,而出现黄疸患者的浸润癌风险高

JAMA Pediatr:每小时15分钟的循环光疗用于治疗极低出生体重新生儿黄疸

每小时15分钟的循环光疗可有效控制极低出生体重新生儿的血清总胆红素水平,同时减少光疗暴露

宝贝黄疸可以接种疫苗吗?

黄疸只是一种症状学上的诊断,它不是一种疾病。婴儿黄疸是婴儿期最常见的临床症状,主要是由于胆红素在体内积累而引起的皮肤、黏膜或其他器官黄染。

NEJM:胆管铸型综合征-病例报道

在该过程中,发现了胆管铸型(见图片),并从胆总管的上端和肝内胆管中取出。胆管铸型综合症的特征是肝移植后出现胆管树铸型。

关于新生儿黄疸 新手爸妈很需要知道的都在这里

新生儿黄疸可能是大部分新手爸妈遭遇的第一个难题,很多家长为这个焦虑不已,作为儿科医生,我也经常接到这样的咨询,因此想和大家谈谈这个话题。黄疸这个事情细说起来很复杂,因为它不是一个疾病,而是一个症状,其背后可能存在的是一系列病理或者生理的情况,涉及到的基础理论知识很多,作为家长不容易也不需要掌握这些复杂的理论,因此,这里我只选择了一些最常被问到的问题,并且尽量少谈理论,多从普通家长的角度去分析,帮助

拓展阅读

一文读懂!胆红素与黄疸解析

对于黄疸大家并不陌生,可什么是黄疸?还有我们体检中必不可少的肝功能中检验中包括的总胆红素、直接胆红素、间接胆红素,它们之间又有什么联系呢?下面,带大家一起了解胆红素的代谢吧。

特别关注|良性肝功能异常的临床意义

一些遗传、免疫因素可引起肝生化指标异常,但并不伴有肝损伤,其远期预后也大多较好,笔者将其命名为“良性肝功能异常”,本文将对此类疾病作一综述。

Immun Inflamm Dis:胆红素与系统性红斑狼疮的关系

系统性红斑狼疮(SLE)是一种世界性的高患病率自身免疫性疾病。本研究旨在探讨血清胆红素水平与SLE的相关性。

胆红素介绍

血清胆红素的测定是肝、胆功能检查中的一项重要检测项目。能准确地反映黄疸的程度,对临床诊断隐性黄疸有重要意义。

生化检验,仅仅看实测值指标就够了?不知道你就out啦,快来看看这些比值指标吧

那么生化检验中有哪些常见而我们又容易忽略的比值指标呢?这些比值指标具有什么临床意义呢?下面让我们一起更深入地认识这些比值指标!!!