The core of β‐lactam antibiotics originates from amino acids of primary metabolism in certain microorganisms. β‐Lactam‐producing bacteria, including Streptomyces clavuligerus, synthesize the precursor of the amino acid α‐aminoadipic acid by the catabolism of lysine in two steps. The second reaction, the oxidation of piperideine‐6‐carboxylate (or its open‐chain form α‐aminoadipate semialdehyde) to α‐aminoadipic acid, is catalysed by the NAD⁺‐dependent enzyme piperideine‐6‐carboxylate dehydrogenase (P6CDH). This structural study, focused on ligand binding and catalysis, presents structures of P6CDH from S. clavuligerus in its apo form and in complexes with the cofactor NAD⁺, the product α‐aminoadipic acid and a substrate analogue, picolinic acid. P6CDH adopts the common aldehyde dehydrogenase fold, consisting of NAD‐binding, catalytic and oligomerization domains. The product binds in the oxyanion hole, close to the catalytic residue Cys299. Clear density is observed for the entire cofactor, including the nicotinamide riboside, in the binary complex. NAD⁺ binds in an extended conformation with its nicotinamide ring overlapping with the binding site of the carboxylate group of the product, implying that the conformation of the cofactor may change during catalysis. The binding site of the substrate analogue overlaps with that of the product, suggesting that the cyclic form of the substrate, piperideine‐6‐carboxylate, may be accepted as a substrate by the enzyme. The catalytic mechanism and the roles of individual residues are discussed in light of these results.

中文翻译：

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克拉维链霉菌哌啶-6-羧酸盐脱氢酶的结构和机理。

β-内酰胺类抗生素的核心源自某些微生物的主要代谢氨基酸。包括棒状链霉菌在内的产生β-内酰胺的细菌可通过赖氨酸的分解代谢分两步合成氨基酸α-氨基己二酸的前体。第二个反应是哌啶-6-羧酸盐（或其开链形式的α-氨基己二酸半醛）氧化为α-氨基己二酸，是由NAD ⁺依赖性酶哌啶-6-6羧酸盐脱氢酶（P6CDH）催化的。这项针对配体结合和催化的结构研究，提出了来自S. clavuligerus的P6CDH的apo形式以及与辅因子NAD ^+的复合物的结构。，产物α-氨基己二酸和底物类似物吡啶甲酸。P6CDH采用常见的醛脱氢酶折叠，由NAD结合，催化和低聚域组成。产物结合在氧阴离子孔中，靠近催化残基Cys299。对于二元复合物中的整个辅助因子，包括烟酰胺核糖苷，均观察到了清晰的密度。NAD ⁺其烟酰胺酰胺环与产物的羧酸酯基团的结合位点重叠而以延长的构象结合，这表明辅酶的构象可能在催化过程中改变。底物类似物的结合位点与产物的结合位点重叠，表明底物的环状形式哌啶子基-6羧酸盐可以被酶接受为底物。鉴于这些结果，讨论了催化机理和各个残基的作用。