A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase PMID: 37296100

GLP-1 and Obesity Research

2026-08-18

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

Nat Commun. 2023 Jun 9;14(1):3392. doi: 10.1038/s41467-023-38467-9.

Vinitha N Ragavan ^# ¹ ² , Pramod C Nair ^# ² ³ ⁴ ⁵ , Natalia Jarzebska ¹ , Ramcharan Singh Angom ⁶ , Luana Ruta ⁷ , Elisa Bianconi ⁷ , Silvia Grottelli ⁸ , Natalia D Tararova ⁹ , Daniel Ryazanskiy ⁹ , Steven R Lentz ¹⁰ , Sara Tommasi ² , Jens Martens-Lobenhoffer ¹¹ , Toshiko Suzuki-Yamamoto ¹² , Masumi Kimoto ¹² , Elena Rubets ¹ , Sarah Chau ¹³ , Yingjie Chen ¹⁴ , Xinli Hu ¹⁵ , Nadine Bernhardt ¹⁶ , Peter M Spieth ¹⁷ , Norbert Weiss ¹ , Stefan R Bornstein ¹ ¹⁸ , Debabrata Mukhopadhyay ⁶ , Stefanie M Bode-Böger ¹¹ , Renke Maas ¹⁹ ²⁰ , Ying Wang ¹³ , Antonio Macchiarulo ⁷ , Arduino A Mangoni ² , Barbara Cellini ⁸ , Roman N Rodionov ²¹ ²²

Affiliations

1. Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany.
2. Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University and Flinders Medical Centre, Bedford Park, Adelaide, SA, Australia.
3. Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
4. Cancer Program, South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide, Adelaide, SA, Australia.
5. Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
6. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL, USA.
7. Department of Pharmaceutical Sciences, University of Perugia, via del Liceo 1, Perugia, Italy.
8. Department of Medicine and Surgery, University of Perugia, P.le L. Sevari 1, Perugia, Italy.
9. DAPCEL, Inc., Cleveland, OH, USA.
10. Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USA.
11. Institute of Clinical Pharmacology, Otto von Guericke University, Magdeburg, Germany.
12. Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, Okayama, Japan.
13. Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, NY, USA.
14. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
15. Institute of Molecular Medicine, Beijing University, Beijing, China.
16. Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
17. Department of Anesthesiology and Critical Care Medicine, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany.
18. School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
19. Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
20. FAU New - Research Center for New Bioactive Compounds, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
21. Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany. [email protected].
22. College of Medicine and Public Health, Flinders University and Flinders Medical Center, Adelaide, SA, Australia. [email protected].
# Contributed equally.

Abstract

Dimethylarginine 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.