Structural and Biochemical Mechanism of ALDH6A1 Uncovered

This study was led by Dr. Xiaodong Luan (Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science), Prof. Shuyang Zhang (Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science), Prof. Limeng Chen (Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College), Dr. Gengchen Su (Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science) and Dr. Kaide Ju (School of Medicine, Tsinghua University)

ALDH6A1, a member of the ALDH family, plays a crucial role in the catabolic pathways of valine and thymine. Dysregulation of ALDH6A1 expression has been linked to a variety of diseases. Methylmalonate semialdehyde dehydrogenase deficiency (MMSDH deficiency), an autosomal recessive disorder, arises from mutations in the ALDH6A1 gene. Additionally, ALDH6A1 has emerged as a biomarker for several types of severe cancer. Despite its significance, the structural and biochemical mechanisms of ALDH6A1 remain poorly explored.

The authors identified a structural and biochemical mechanism of ALDH6A1. A structural analysis of ALDH6A1 in its apo form at a resolution of 2.75 Å uncovered a tetrameric architecture with tightly interacting monomers. Their findings also indicated that Alda-1, an agonist of ALDH2, enhanced ALDH6A1 activity as well.

Furthermore, the authors showed that ALDH6A1, compared with ALDH2, exhibited a unique binding model with NAD⁺. These findings might hold promise for the development of targeted therapies aimed at restoring ALDH6A1 activity, thus providing potential value for individuals affected by related diseases.

Our work for the first time identifies the structure of the ALDH6A1 apo form, the interaction mechanism between ALDH6A1 and NAD⁺ by molecular docking, and Alda-1 as an agonist for ALDH6A1. The study for the structural and biochemical mechanism of ALDH6A1 could lay the groundwork for developing targeted therapies to restore ALDH6A1 activity, potentially benefiting individuals affected by related diseases."

Dr. Xiaodong Luan, corresponding author