Metallo-β-lactamase Domain-Containing Protein 1 (MBLAC1) Is a Specific, High-Affinity Target for the Glutamate Transporter Inducer Ceftriaxone,ACS Chemical Neuroscience

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Metallo-β-lactamase Domain-Containing Protein 1 (MBLAC1) Is a Specific, High-Affinity Target for the Glutamate Transporter Inducer Ceftriaxone
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-08-14 00:00:00 , DOI: 10.1021/acschemneuro.7b00232
Cassandra L. Retzlaff ₁ , Amanda Kussrow , Tim Schorkopf , Phoonthawee Saetear , Darryl J. Bornhop , J. Andrew Hardaway , Sarah M. Sturgeon , Jane Wright , Randy D. Blakely ₁

Affiliation

Ceftriaxone, a β-lactam antibiotic, has been reported to act independently of its antimicrobial actions to normalize perturbed central nervous system glutamate levels, principally by elevating expression of glial glutamate transporters. Identification of a specific, high-affinity target for ceftriaxone could significantly impact therapeutic development for multiple brain disorders, ranging from neurodegenerative disorders to addiction. Recently, we identified a glial-expressed Caenorhabditis elegans gene, swip-10, that encodes a metallo-β-lactamase domain-containing protein, and limits glutamate-dependent changes in dopamine neuron excitability. Bioinformatic analyses identified MBLAC1 as the likely mammalian orthologue of swip-10. Using cyanogen bromide immobilized ceftriaxone for affinity capture experiments and backscattering interferometry to monitor MBLAC1 binding of unmodified ceftriaxone, we obtained evidence for specific, high affinity (K_D = 2.2 μM) binding of ceftriaxone to MBLAC1. We discuss our findings with respect to MBLAC1 as a potentially exclusive, high-affinity binding partner of ceftriaxone in the CNS, and the path forward in the development of novel, MBLAC1-based therapeutics.

中文翻译：

金属-β-内酰胺酶域蛋白1（MBLAC1）是谷氨酸转运蛋白诱导剂头孢曲松钠的特异，高亲和力靶标

据报道，头孢曲松是一种β-内酰胺类抗生素，其抗菌作用独立于正常化受扰的中枢神经系统谷氨酸水平，主要是通过提高神经胶质谷氨酸转运蛋白的表达来发挥作用。头孢曲松钠的特异性，高亲和力靶标的鉴定可能会严重影响从神经退行性疾病到成瘾的多种脑部疾病的治疗发展。最近，我们鉴定了一种神经胶质细胞表达的秀丽隐杆线虫基因swip-10，该基因编码含有金属β-内酰胺酶结构域的蛋白质，并限制了谷氨酸依赖的多巴胺神经元兴奋性变化。生物信息学分析确定MBLAC1是swip-10的可能的哺乳动物直系同源物。使用溴化氰固定的头孢曲松钠进行亲和力捕获实验和反向散射干涉测量法监测未修饰的头孢曲松钠的MBLAC1结合，我们获得了头孢曲松酮与MBLAC1特异性，高亲和力（K _D = 2.2μM）结合的证据。我们讨论了关于MBLAC1作为中枢神经系统中头孢曲松酮的潜在排他性，高亲和力结合伴侣的发现，以及开发基于MBLAC1的新型疗法的发展道路。

更新日期：2017-08-15

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