UMR 7365, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), CNRS-Université de Lorraine, Biopôle de l'Université de Lorraine, Campus Biologie Santé, 9 Avenue de la Forêt de Haye, BP 20199, 54505, Vandœuvre-lès-Nancy Cedex, France.
Sorbonne Universités, UPMC Univ. Paris 06, CNRS, UMR 8227, Integrative Biology of Marine Models, Station Biologique de Roscoff, CS 90074, Roscoff, Bretagne, France.
Nat Commun. 2018 Sep 28;9(1):3998. doi: 10.1038/s41467-018-06323-w.
Acquisition of new catalytic activity is a relatively rare evolutionary event. A striking example appears in the pathway to the antibiotic lankacidin, as a monoamine oxidase (MAO) family member, LkcE, catalyzes both an unusual amide oxidation, and a subsequent intramolecular Mannich reaction to form the polyketide macrocycle. We report evidence here for the molecular basis for this dual activity. The reaction sequence involves several essential active site residues and a conformational change likely comprising an interdomain hinge movement. These features, which have not previously been described in the MAO family, both depend on a unique dimerization mode relative to all structurally characterized members. Taken together, these data add weight to the idea that designing new multifunctional enzymes may require changes in both architecture and catalytic machinery. Encouragingly, however, our data also show LkcE to bind alternative substrates, supporting its potential utility as a general cyclization catalyst in synthetic biology.
获得新的催化活性是一个相对罕见的进化事件。在抗生素 lankacidin 的途径中，出现了一个引人注目的例子，作为单胺氧化酶（MAO）家族成员的 LkcE，同时催化了一种不寻常的酰胺氧化，以及随后的分子内曼尼希反应，形成了聚酮大环。我们在这里报告了这种双重活性的分子基础的证据。反应序列涉及几个必需的活性位点残基和构象变化，可能包括结构域间铰链运动。这些特征以前在 MAO 家族中没有描述过，它们都依赖于相对于所有结构特征成员的独特二聚化模式。这些数据共同表明，设计新的多功能酶可能需要改变结构和催化机制。然而，令人鼓舞的是，我们的数据还表明 LkcE 可以结合替代底物，支持其作为合成生物学中通用环化催化剂的潜在用途。
