Lysine L-lactylation is the dominant lactylation isomer induced by glycolysis PMID: 39030363

ADC Targets in Oncology

2026-04-10

Lysine L-lactylation is the dominant lactylation isomer induced by glycolysis

Nat Chem Biol. 2024 Jul 19. doi: 10.1038/s41589-024-01680-8.

Di Zhang ^# ¹ ² , Jinjun Gao ^# ³ ⁴ ⁵ , Zhijun Zhu ^# ⁶ , Qianying Mao ⁷ ⁸ , Zhiqiang Xu ⁹ , Pankaj K Singh ¹⁰ , Cornelius C Rimayi ¹⁰ , Carlos Moreno-Yruela ¹¹ , Shuling Xu ¹² , Gongyu Li ¹² ¹³ , Yi-Cheng Sin ¹⁴ , Yue Chen ¹⁴ , Christian A Olsen ¹¹ , Nathaniel W Snyder ¹⁰ , Lunzhi Dai ¹⁵ , Lingjun Li ¹⁶ ¹⁷ , Yingming Zhao ¹⁸

Affiliations

1. State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China. [email protected].
2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. [email protected].
3. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
4. State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
5. Shenzhen Bay Laboratory, Shenzhen, China.
6. Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA.
7. State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
8. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
9. National Clinical Research Center for Geriatrics and General Practice Ward/International Medical Center Ward, General Practice Medical Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
10. Lewis Katz School of Medicine at Temple University, Department of Cardiovascular Sciences, Center for Metabolic Disease Research, Philadelphia, PA, USA.
11. Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
12. School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA.
13. Research Center for Analytical Science and Tianjin Key Laboratory of Biosensing and Molecular Recognition, College of Chemistry, Nankai University, Tianjin, China.
14. Department of Biochemistry, Molecular Biology and Biophysics, The University of Minnesota at Twin Cities, Minneapolis, MN, USA.
15. National Clinical Research Center for Geriatrics and General Practice Ward/International Medical Center Ward, General Practice Medical Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. [email protected].
16. Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA. [email protected].
17. School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA. [email protected].
18. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA. [email protected].
# Contributed equally.

Abstract

Lysine L-lactylation (K_l-la) is a novel protein posttranslational modification (PTM) driven by L-lactate. This PTM has three isomers: K_l-la, N-ε-(carboxyethyl)-lysine (K_ce) and D-lactyl-lysine (K_d-la), which are often confused in the context of the Warburg effect and nuclear presence. Here we introduce two methods to differentiate these isomers: a chemical derivatization and high-performance liquid chromatography analysis for efficient separation, and isomer-specific antibodies for high-selectivity identification. We demonstrated that K_l-la is the primary lactylation isomer on histones and dynamically regulated by glycolysis, not K_d-la or K_ce, which are observed when the glyoxalase system was incomplete. The study also reveals that lactyl-coenzyme A, a precursor in L-lactylation, correlates positively with K_l_-la levels. This work not only provides a methodology for distinguishing Other PTM isomers, but also highlights K_l-la as the primary responder to glycolysis and the Warburg effect.