Dihydroorotate:quinone oxidoreductases (DHOQOs) are membrane bound enzymes responsible for oxidizing dihydroorotate (DHO) to orotate with concomitant reduction of quinone to quinol. They have FMN as prosthetic group and are part of the monotopic quinone reductase superfamily. These enzymes are also members of the dihydroorotate dehydrogenases (DHODHs) family, which besides membrane bound DHOQOs, class 2, includes soluble enzymes which reduce either NAD⁺ or fumarate, class 1. As key enzymes in both the de novo pyrimidine biosynthetic pathway as well as in the energetic metabolism, inhibitors of DHOQOs have been investigated as leads for therapeutics in cancer, immunological disorders and bacterial/viral infections. This work is a thorough bioinformatic approach on the structural conservation and taxonomic distribution of DHOQOs. We explored previously established structural/functional hallmarks of these enzymes, while searching for uncharacterized common elements. We also discuss the cellular role of DHOQOs and organize the identified protein sequences within six sub-classes 2A to 2F, according to their taxonomic origin and sequence traits. We concluded that DHOQOs are present in Archaea, Eukarya and Bacteria, including the first recognition in Gram-positive organisms. DHOQOs can be the single dihydroorotate dehydrogenase encoded in the genome of a species, or they can coexist with other DHODHs, as the NAD⁺ or fumarate reducing enzymes. Furthermore, we show that the type of catalytic base present in the active site is not an absolute criterium to distinguish between class 1 and class 2 enzymes. We propose the existence of a quinone binding motif (“ExAH”) adjacent to a hydrophobic cavity present in the membrane interacting N-terminal domain.

二氢乳清酸酯：醌氧化还原酶（DHOQO）是膜结合酶，负责将二氢乳清酸酯（DHO）氧化为乳清酸酯，同时将醌还原为喹诺酮。他们以FMN为假肢，并且是单端醌还原酶超家族的一部分。这些酶也二氢乳清脱氢酶（DHODHs）家族，其除了膜结合DHOQOs，类2，包括可溶性酶，其减少或者NAD的成员⁺或富马酸盐，类1.由于在两个关键酶从头嘧啶的生物合成途径以及能量代谢方面，已经研究了DHOQOs抑制剂作为癌症，免疫性疾病和细菌/病毒感染的治疗药物。这项工作是对DHOQO的结构保护和分类分布进行彻底的生物信息学研究。我们探索了这些酶先前建立的结构/功能标志，同时寻找了未表征的常见元素。我们还讨论了DHOQO的细胞作用，并根据它们的分类学起源和序列特征，在6个亚类2A至2F中组织了鉴定出的蛋白质序列。我们得出的结论是，古生菌，Eukarya和细菌中都存在DHOQO，包括在革兰氏阳性生物中的首次识别。⁺或富马酸酯还原酶。此外，我们表明存在于活性位点的催化碱的类型不是区分1类和2类酶的绝对标准。我们提出存在与膜相互作用的N-末端结构域中存在的疏水腔相邻的醌结合基序（“ ExAH”）。