Repurposing Styrene Catabolic Enzymes for the Synthesis of Penicillins

重新利用苯乙烯分解代谢酶来合成青霉素

基本信息

  • 批准号:
    10411114
  • 负责人:
  • 金额:
    $ 15.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-20 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Abstract Penicillins represent one of the most impactful antibiotics in use for the resolution of gram-positive bacterial infections including bacterial meningitis, diptheria, strep throat, syphilis, gonorrhea, and yaws disease that afflict more than 6 million people annually. These antibiotics are frequently in short supply and improved production methods are needed that both increase the accessibility while reducing inefficiency and environmental impacts associated with current production methods. The primary route to the commercial production of penicillins begins with batch fermentation of the fungus, P. chrysogenum as a biosynthetic route to 6-aminopenicillanic acid (6-APA), which is subsequently used as a starting material for the synthesis of b-lactam antibiotics. As an alternative to currently employed organic synthetic routes to amidation of 6-APA, chemoenzymatic synthetic methods based on the amidation of 6-APA by penicillin amidases (PAs) or isopenicillanic acid transferases (IATs) provide a competitive green chemical approach to penicillin-based antibiotics. Each chemoenzymatic approach poses unique challenges. The amidase-catalyzed acylation of 6-APA requires the use of chemically activated carboxylic acid derivatives as substrates and proceeds with low transformation efficiency. IATs on the other hand are dependent on phenylacetyl- Coenzyme A ligases, which have low stability and limited substrate specificity. In the present work we target an alternate chemoenzymatic strategy for the synthesis of penicillins from aldehydes by joining the activities of IAT and an engineered thiol-acylating aldehyde dehydrogenase (TAD). The first specific aim of this work will target the selective introduction of mutations in the catalytic active site of phenylacetaldehyde dehydrogenase (NPADH) from Pseudomonas putidia (S12), which has a broad aldehyde specificity. Mutations will target the transformation of NPADH into a TAD for the synthesis of the N-acetylcysteamine (SNAc) thioesters. In our second aim, SNAc thiosesters, which are surrogates of acyl-CoA will be introduced with 6- APA co-substrates in the IAT-catalyzed synthesis of penicillins. This strategy is expected to result in a high product yield while eliminating the limitations associated with the phenylacetyl CoA ligases. The development this process will serve as prototypical green-chemistry pathway that can be further expanded into a platform for the production of existing and new classes of b-lactam antibiotics.
摘要 青霉素是目前用于革兰氏阳性菌分离的最有效的抗生素之一 感染包括细菌性脑膜炎、白喉、链球菌性咽喉炎、梅毒、淋病和雅司病 每年有600多万人。这些抗生素经常供不应求,产量也有所提高。 需要既增加可访问性又减少低效和对环境影响的方法 与当前的生产方法相关联。青霉素商业化生产的主要途径开始了 通过分批发酵该真菌,产黄假单胞菌作为生物合成6-氨基青霉酸(6-APA)的路线, 随后将其用作合成β-内酰胺类抗生素的起始原料。作为替代方案 目前采用的有机合成路线是6-APA的酰胺化,化学酶法合成的方法是 青霉素酰胺酶(Pas)或异青霉烷酸转移酶(Iats)对6-APA的酰胺化提供了一种具有竞争力的 青霉素类抗生素的绿色化学方法。每一种化学酶方法都带来了独特的挑战。 酰胺酶催化的6-APA的酰化反应需要使用化学活化的羧酸衍生物 底物,转化效率低。另一方面,IATS依赖于苯乙酰- 辅酶A连接酶,稳定性低,底物专一性有限。 在目前的工作中,我们的目标是一种替代的化学酶策略来合成青霉素类药物 通过加入IAT和工程硫醇酰化醛脱氢酶(TAD)的活性来合成醛。第一 这项工作的具体目标是选择性地在催化活性部位引入突变 恶臭假单胞菌(S12)苯乙醛脱氢酶(NPADH) 专一性。突变的目标是将NPADH转化为TAD以合成N-乙酰半胱胺 (SNAC)硫代酯。在我们的第二个目标中,作为酰基-CoA的替代品的SNAC硫酯将被引入6- APA共底物在IAT催化合成青霉素中的应用。这一战略有望带来高产量。 同时消除与苯乙酰CoA连接酶相关的限制。发展这一过程 将作为典型的绿色化学途径,可以进一步扩展为生产平台 现有的和新的β-内酰胺类抗生素。

项目成果

期刊论文数量(0)
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George T. Gassner其他文献

<em>De novo</em> design of functional Mn-porphyrin binding proteins
  • DOI:
    10.1016/j.bpj.2021.11.1946
  • 发表时间:
    2022-02-11
  • 期刊:
  • 影响因子:
  • 作者:
    Samuel I. Mann;Animesh Nayak;George T. Gassner;Michael J. Therien;William F. DeGrado
  • 通讯作者:
    William F. DeGrado

George T. Gassner的其他文献

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{{ truncateString('George T. Gassner', 18)}}的其他基金

Repurposing Styrene Catabolic Enzymes for the Synthesis of Penicillins
重新利用苯乙烯分解代谢酶来合成青霉素
  • 批准号:
    10686815
  • 财政年份:
    2022
  • 资助金额:
    $ 15.5万
  • 项目类别:
Structure and Mechanisms of Styrene Monooxygenase
苯乙烯单加氧酶的结构和机制
  • 批准号:
    7488409
  • 财政年份:
    2007
  • 资助金额:
    $ 15.5万
  • 项目类别:
Structure and Mechanisms of Styrene Monooxygenase
苯乙烯单加氧酶的结构和机制
  • 批准号:
    7678363
  • 财政年份:
    2007
  • 资助金额:
    $ 15.5万
  • 项目类别:
Structure and Mechanisms of Styrene Monooxygenase
苯乙烯单加氧酶的结构和机制
  • 批准号:
    7910560
  • 财政年份:
    2007
  • 资助金额:
    $ 15.5万
  • 项目类别:
Structure and Mechanisms of Styrene Monooxygenase
苯乙烯单加氧酶的结构和机制
  • 批准号:
    7289486
  • 财政年份:
    2007
  • 资助金额:
    $ 15.5万
  • 项目类别:
Ligand-Binding in the Reaction Mechanism of DAO
DAO 反应机制中的配体结合
  • 批准号:
    6596457
  • 财政年份:
    2003
  • 资助金额:
    $ 15.5万
  • 项目类别:
Ligand-Binding in the Reaction Mechanism of DAO
DAO 反应机制中的配体结合
  • 批准号:
    6838246
  • 财政年份:
    2003
  • 资助金额:
    $ 15.5万
  • 项目类别:
NMR SOLUTION STRUCTURE OF THE MMOB COMPONENT
MMOB 组件的 NMR 解决方案结构
  • 批准号:
    2910033
  • 财政年份:
    1999
  • 资助金额:
    $ 15.5万
  • 项目类别:
NMR SOLUTION STRUCTURE OF THE MMOB COMPONENT
MMOB 组件的 NMR 解决方案结构
  • 批准号:
    2521187
  • 财政年份:
    1998
  • 资助金额:
    $ 15.5万
  • 项目类别:

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