Heme proteins of the protozoan parasite Giardia intestinalis

原生动物寄生虫肠贾第鞭毛虫的血红素蛋白

• 批准号: RGPIN-2018-04165
• 负责人: Rafferty, Steven
• 金额: $ 2.33万
• 依托单位: Trent University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748059
• 关键词: Heme; proteins; protozoan; parasite; Giardia

Heme is a biomolecular tool whose purpose depends on the protein that wields it. Its most famous role is as the oxygen-binding site in hemoglobin of our red blood cells. However, heme has many other roles as well, and for most organisms it is indispensable. Until recently, the protozoan parasite Giardia intestinalis was thought to be one of the rare organisms that did not need heme, as it lacked key enzymes that require this cofactor. However, the genome of Giardia intestinalis has genes for several heme proteins: a flavohemoglobin and four members of the cytochrome b5 family of electron transfer proteins. Both sets of proteins have unusual features that are not found in other family members. Flavohemoglobins are found in bacteria and fungi where they protect the microbe from nitric oxide by converting it to harmless nitrate. The Giardia protein likely has the same role, but its amino acid sequence is larger due to inserts within the heme-binding globin domain and the flavoprotein domain. We are interested in what this difference, and others within the heme-binding site, may have on the functional properties of Giardia protein, and whether these differences could lead to the design of agents that inhibit the Giardia protein without affecting the flavohemoglobin of benign microorganisms that are also found in the gut. The Giardia cytochromes b5 are also interesting because they lack features commonly associated with other family members, yet have other features that are unique to them. They are also found within the cell in locations not typically associated with cytochromes b5, and they have no known function. We suspect that the differences that the Giardia cytochromes exhibit are connected to their as-yet undiscovered functions, and we are trying to understand this connection by examining the properties of the Giardia cytochromes and altered versions that we have prepared. Finally, we are searching for additional heme proteins that may have escaped easy identification because they are so distantly related to their relatives. With our work we will have a fuller understanding of the biochemistry of an important human and animal pathogen, and potentially reveal new biochemical pathways and processes for other researchers to follow.

血红素是一种生物分子工具，其用途取决于使用它的蛋白质。它最著名的作用是作为我们红细胞中的血红蛋白的氧结合部位。然而，血红素还有许多其他作用，对于大多数生物体来说，它是不可或缺的。直到最近，原生动物寄生虫肠贾第鞭毛虫被认为是罕见的不需要血红素的生物之一，因为它缺乏需要这种辅因子的关键酶。然而，肠贾第鞭毛虫的基因组有几种血红素蛋白的基因：一种黄色素和四种细胞色素b5电子转移蛋白家族的成员。这两组蛋白质都有其他家族成员没有的不同寻常的特征。黄红蛋白存在于细菌和真菌中，它们通过将微生物转化为无害的硝酸盐来保护微生物免受一氧化氮的伤害。贾第虫蛋白可能具有相同的作用，但它的氨基酸序列更大，因为它插入了与血红素结合的珠蛋白结构域和黄素蛋白结构域。我们感兴趣的是，这种差异以及血红素结合位点上的其他差异可能对贾第虫蛋白的功能特性产生了什么影响，以及这些差异是否会导致设计出抑制贾第虫蛋白的药物，而不会影响肠道中也发现的良性微生物的黄色素。贾第鞭毛虫细胞色素b5也很有趣，因为它们缺乏与其他家庭成员共同相关的特征，但具有它们独有的其他特征。它们也在细胞内通常与细胞色素b5无关的位置被发现，并且它们没有已知的功能。我们怀疑贾第鞭毛虫细胞色素的差异与它们尚未发现的功能有关，我们正试图通过检查贾第鞭毛虫细胞色素的性质和我们准备的改变后的版本来理解这种联系。最后，我们正在寻找其他可能逃脱了容易识别的血红素蛋白，因为它们与亲戚关系太远了。通过我们的工作，我们将对一种重要的人类和动物病原体的生物化学有更全面的了解，并可能揭示新的生化途径和过程，供其他研究人员效仿。