Defects in inosine monophosphate dehydrogenase-1 (IMPDH1) lead to insufficient biosyntheses of purine nucleotides. In eyes, these defects are believed to cause retinitis pigmentosa (RP). Major retinal isoforms of IMPDH1 are structurally distinct from those in other tissues, by bearing terminal extensions. Using recombinant mouse IMPDH1 (mH1), we evaluated the kinetics and oligomerization states of the retinal isoforms. Moreover, we adopted molecular simulation tools to study the possible effect of terminal tails on the function of major enzyme isoforms with the aim to find structural evidence in favor of contradictory observations on retinal IMPDH1 function. Our findings indicated higher catalytic activity for the major mouse retinal isoform (mH1603) along with lower fibrillation capacity under the influence of ATP. However, higher mass oligomerization products were formed by the mH1 (603) isoform in the presence of the enzyme inhibitors such as GTP and/or MPA. Collectively, our findings demonstrate that the structural differences between the retinal isoforms have led to functional variations possibly to justify the retinal cells’ requirements.

肌苷单磷酸脱氢酶-1 (IMPDH1) 的缺陷导致嘌呤核苷酸的生物合成不足。在眼睛中，这些缺陷被认为会导致视网膜色素变性 (RP)。IMPDH1 的主要视网膜异构体在结构上与其他组织中的异构体不同，因为它们具有末端延伸。使用重组小鼠 IMPDH1 (mH1)，我们评估了视网膜异构体的动力学和寡聚化状态。此外，我们采用分子模拟工具来研究末端尾部对主要酶同种型功能的可能影响，目的是找到有利于对视网膜 IMPDH1 功能进行矛盾观察的结构证据。我们的研究结果表明，在 ATP 的影响下，主要小鼠视网膜亚型 (mH1603) 具有更高的催化活性以及更低的纤颤能力。然而，在酶抑制剂如 GTP 和/或 MPA 存在下，mH1 (603) 异构体形成更高质量的寡聚化产物。总的来说，我们的研究结果表明，视网膜同种型之间的结构差异导致了功能变化，可能证明视网膜细胞的需求是合理的。