Pirovich David B, Da'dara Akram A, Skelly Patrick J
Molecular Helminthology Laboratory, Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, United States.
Front Mol Biosci. 2021 Aug 11;8:719678. doi: 10.3389/fmolb.2021.719678. eCollection 2021.
Fructose 1,6-bisphosphate aldolase is a ubiquitous cytosolic enzyme that catalyzes the fourth step of glycolysis. Aldolases are classified into three groups: Class-I, Class-IA, and Class-II; all classes share similar structural features but low amino acid identity. Apart from their conserved role in carbohydrate metabolism, aldolases have been reported to perform numerous non-enzymatic functions. Here we review the myriad "moonlighting" functions of this classical enzyme, many of which are centered on its ability to bind to an array of partner proteins that impact cellular scaffolding, signaling, transcription, and motility. In addition to the cytosolic location, aldolase has been found the extracellular surface of several pathogenic bacteria, fungi, protozoans, and metazoans. In the extracellular space, the enzyme has been reported to perform virulence-enhancing moonlighting functions e.g., plasminogen binding, host cell adhesion, and immunomodulation. Aldolase's importance has made it both a drug target and vaccine candidate. In this review, we note the several inhibitors that have been synthesized with high specificity for the aldolases of pathogens and cancer cells and have been shown to inhibit classical enzyme activity and moonlighting functions. We also review the many trials in which recombinant aldolases have been used as vaccine targets against a wide variety of pathogenic organisms including bacteria, fungi, and metazoan parasites. Most of such trials generated significant protection from challenge infection, correlated with antigen-specific cellular and humoral immune responses. We argue that refinement of aldolase antigen preparations and expansion of immunization trials should be encouraged to promote the advancement of promising, protective aldolase vaccines.
果糖-1,6-二磷酸醛缩酶是一种普遍存在于细胞质中的酶，它催化糖酵解的第四步。醛缩酶分为三类：I类、IA类和II类；所有类别都具有相似的结构特征，但氨基酸同源性较低。除了在碳水化合物代谢中发挥保守作用外，醛缩酶还被报道具有多种非酶功能。在此，我们综述了这种经典酶的众多“兼职”功能，其中许多功能集中在其与一系列影响细胞支架、信号传导、转录和运动的伴侣蛋白结合的能力上。除了细胞质定位外，醛缩酶还存在于几种致病细菌、真菌、原生动物和后生动物的细胞外表面。在细胞外空间，该酶被报道具有增强毒力的“兼职”功能，例如纤溶酶原结合、宿主细胞粘附和免疫调节。醛缩酶的重要性使其成为药物靶点和疫苗候选物。在本综述中，我们提到了几种针对病原体和癌细胞醛缩酶合成的高特异性抑制剂，这些抑制剂已被证明可抑制经典酶活性和“兼职”功能。我们还综述了许多试验，其中重组醛缩酶被用作针对包括细菌、真菌和后生动物寄生虫在内的多种致病生物的疫苗靶点。大多数此类试验都产生了显著的针对攻击感染的保护作用，这与抗原特异性细胞免疫和体液免疫反应相关。我们认为应鼓励改进醛缩酶抗原制剂并扩大免疫试验，以促进有前景的、具有保护作用的醛缩酶疫苗的发展。
