A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase

• DOI: 10.1038/s41467-023-38467-9
• Publication Date: 2023-06-09T05:02:25Z
• Authors: Vinitha N. Ragavan; Pramod C. Nair; Natalia Jarzebska; Ramcharan Singh A...; Luana Ruta; Elisa Bianconi; Silvia Grottelli; Natalia D. Tararova; Daniel Ryazanskiy; Steven R. Lentz; Sara Tommasi; Jens Martens-Lobe...; Toshiko Suzuki-Ya...; Masumi Kimoto; Elena Rubets; Sarah Chau; Yingjie Chen; Xinli Hu; Nadine Bernhardt; Peter M. Spieth; Norbert Weiss; Stefan R. Bornstein; Debabrata Mukhopa...; Stefanie M. Bode-...; Renke Maas; Ying Wang; Antonio Macchiarulo; Arduino A. Mangoni; Barbara Cellini; Roman N. Rodionov
• Keywords: Science; Q; 10265 Clinic for Endocrinology and Diabetology; 610 Medicine & health; 1600 General Chemistry; Arginine; Nitric Oxide; 3100 General Physics and Astronomy; Article; 3. Good health; Amidohydrolases; Mice; 1300 General Biochemistry, Genetics and Molecular Biology; Animals

AbstractDimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.