Molecular Helminthology Laboratory, Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, U.S.A.
Biochem J. 2022 Jun 17;479(11):1165-1180. doi: 10.1042/BCJ20210784.
Infection with schistosomes (blood flukes) can result in the debilitating disease schistosomiasis. These parasites survive in their host for many years, and we hypothesize that proteins on their tegumental surface, interacting with the host microenvironment, facilitate longevity. One such ectoenzyme - the nucleotide pyrophosphatase/phosphodiesterase SmNPP5 can cleave ADP (to prevent platelet aggregation) and NAD (likely preventing Treg apoptosis). A second tegumental ectoenzyme, the glycohydrolase SmNACE, also catabolizes NAD. Here, we undertake a comparative biochemical characterization of these parasite ectoenzymes. Both are GPI-linked and exhibit different optimal pH ranges. While SmNPP5 requires divalent cations, SmNACE does not. The KM values of the two enzymes for NAD at physiological pH differ: SmNPP5, KM = 340 µM ± 44; SmNACE, KM = 49 µM ± 4. NAD cleavage by each enzyme yields different products. SmNPP5 cleaves NAD to form nicotinamide mononucleotide (NMN) and AMP, whereas SmNACE cleaves NAD to generate nicotinamide (NAM) and adenosine diphosphate ribose (ADPR). Each enzyme can process the other's reaction product. Thus, SmNACE cleaves NMN (to yield NAM and ribose phosphate) and SmNPP5 cleaves ADPR (yielding AMP and ribose phosphate). Metabolomic analysis of plasma containing adult worms supports the idea that these cleavage pathways are active in vivo. We hypothesize that a primary function of SmNPP5 is to cleave NAD to control host immune cell function and a primary function of SmNACE is to cleave NMN to generate the vital nutrient nicotinamide (vitamin B3) for convenient uptake by the worms. Chemical inhibition of one or both ectoenzymes could upset worm metabolism and control schistosome infection.
血吸虫（血吸）感染可导致使人虚弱的疾病血吸虫病。这些寄生虫在宿主中存活多年，我们假设它们表皮表面的蛋白质与宿主微环境相互作用，促进了它们的长寿。其中一种外切酶 - 核苷酸焦磷酸酶/磷酸二酯酶 SmNPP5 可以切割 ADP（防止血小板聚集）和 NAD（可能防止 Treg 细胞凋亡）。第二种表皮外切酶，糖水解酶 SmNACE，也分解 NAD。在这里，我们对这些寄生虫外切酶进行了比较生化特性分析。两者都是 GPI 连接的，具有不同的最适 pH 范围。虽然 SmNPP5 需要二价阳离子，但 SmNACE 不需要。两种酶在生理 pH 下对 NAD 的 KM 值不同：SmNPP5，KM = 340 μM ± 44；SmNACE，KM = 49 μM ± 4。两种酶对 NAD 的切割产物不同。SmNPP5 将 NAD 切割生成烟酰胺单核苷酸（NMN）和 AMP，而 SmNACE 将 NAD 切割生成烟酰胺（NAM）和腺苷二磷酸核糖（ADPR）。每种酶都可以处理另一种酶的反应产物。因此，SmNACE 切割 NMN（生成 NAM 和核糖磷酸），SmNPP5 切割 ADPR（生成 AMP 和核糖磷酸）。含有成虫的血浆代谢组学分析支持这些切割途径在体内活跃的观点。我们假设 SmNPP5 的主要功能是切割 NAD 以控制宿主免疫细胞功能，SmNACE 的主要功能是切割 NMN 以生成重要营养物质烟酰胺（维生素 B3），便于寄生虫摄取。一种或两种外切酶的化学抑制可能会扰乱蠕虫的新陈代谢并控制血吸虫感染。
