# Monoaminylation in Human Health and Disease: State of the Field, Challenges, and Emerging Directions

## TL;DR

This review explores how monoamines modify proteins, influencing gene activity and disease, and highlights their potential for new therapies.

## Contribution

The paper provides a comprehensive overview of monoaminylation mechanisms and their roles in health and disease, emphasizing therapeutic potential.

## Key findings

- Monoaminylation includes serotonylation, dopaminylation, and histaminylation, affecting both histone and non-histone proteins.
- These modifications regulate gene transcription and protein function, with implications in various diseases.
- The paper identifies challenges and suggests future research directions for translational applications.

## Abstract

Parallel to their roles in regulating receptor activation, mounting evidence suggests that monoamines are involved in protein post‐translational modification, which regulates the physiological function of the nervous system and various pathophysiologically relevant conditions. These modifications, primarily including serotonylation, dopaminylation, and histaminylation, occur on both histone and non‐histone proteins, thereby modulating gene transcription and protein function. This review comprehensively summarizes the types of monoaminylation, the catalytic enzymes and molecular mechanisms, and the corresponding monoamine transporters. Furthermore, we categorize and discuss the roles of monoaminylation across the human body in health and disease, highlighting their functional implications and therapeutic potential. We emphasize the need for precise methodologies to modulate monoamine levels in the context of pathological processes across various diseases. Finally, we outline persistent challenges in the field and suggest promising directions for future research, aiming to facilitate both mechanistic insight and translational applications.

This review delineates monoaminylation—serotonylation, dopaminylation, and histaminylation—as key post‐translational modifications beyond receptor signaling. It details their catalytic mechanisms, roles in gene expression and protein function, and implications in health and disease, aiming to bridge mechanistic insights with therapeutic potential.