Studies of lysine cyclodeaminase from Streptomyces pristinaespiralis: Insights into the complex transition NAD+ state
- State Key Laboratory of Materials Oriented Chemical Engineering, Nanjing 211816, PR (China)
- School of Life Science and Biotechnology, Shanghai Jiao-Tong University, PR (China)
Highlights: • LCD and its three structure complexes are determined for the first time. • A NAD{sup +} gate function was revealed in LCD by combining molecular simulation methods. • A substrate tunnel towards NAD{sup +} was observed in LCD via alignment of structures. • This study expands our understanding of catalytic NAD{sup +} usage in various enzymes. Lysine cyclodeaminase (LCD) catalyzes the piperidine ring formation in macrolide-pipecolate natural products metabolic pathways from a lysine substrate through a combination of cyclization and deamination. This enzyme belongs to a unique enzyme class, which uses NAD{sup +} as the catalytic prosthetic group instead of as the co-substrate. To understand the molecular details of NAD{sup +} functions in lysine cyclodeaminase, we have determined four ternary crystal structure complexes of LCD-NAD{sup +} with pipecolic acid (LCD-PA), lysine (LCD-LYS), and an intermediate (LCD-INT) as ligands at 2.26-, 2.00-, 2.17- and 1.80 Å resolutions, respectively. By combining computational studies, a NAD{sup +}-mediated “gate keeper” function involving NAD{sup +}/NADH and Arg49 that control the binding and entry of the ligand lysine was revealed, confirming the critical roles of NAD{sup +} in the substrate access process. Further, in the gate opening form, a substrate delivery tunnel between ε-carboxyl moiety of Glu264 and the α-carboxyl moiety of Asp236 was observed through a comparison of four structure complexes. The LCD structure details including NAD{sup +}-mediated “gate keeper” and substrate tunnel may assist in the exploration the NAD{sup +} function in this unique enzyme class, and in regulation of macrolide-pipecolate natural product synthesis.
- OSTI ID:
- 23100631
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 495, Issue 1; Other Information: Copyright (c) 2017 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
Similar Records
Crystal Structure of Human Dihydrolipoamide Dehydrogenase: NAD[superscript +]/NADH Binding and the Structural Basis of Disease-causing Mutations
Two-metal versus one-metal mechanisms of lysine adenylylation by ATP-dependent and NAD+-dependent polynucleotide ligases