Residues that influence coenzyme preference in the aldehyde dehydrogenases

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Aldehyde dehydrogenases (ALDHs) are crucial enzymes involved in various metabolic pathways.
• ALDHs exhibit varying preferences for nicotinamide adenine dinucleotide (NAD(+)) and its phosphorylated form (NADP(+)) as coenzymes.
• Understanding coenzyme specificity is vital for elucidating ALDH function and designing targeted inhibitors.

Purpose of the Study:

• To identify specific amino acid residues responsible for determining the coenzyme preference of aldehyde dehydrogenases.
• To correlate structural features with kinetic parameters for NAD(+) and NADP(+) binding in ALDHs.

Main Methods:

• Comparative analysis of crystal structures and amino acid sequences of ALDHs.
• Correlation of structural data with published kinetic parameters for NAD(+) and NADP(+) utilization.
• Identification of key residues influencing coenzyme binding through structural and sequence analysis.

Main Results:

• Residue at position 195 (human ALDH2 numbering) is the primary determinant of coenzyme specificity.
• Specific residues like glutamate and proline at position 195 favor NAD(+) binding by repelling NADP(+).
• Flexibility at position 195 and interactions with other residues (e.g., 224, 53) can allow NADP(+) binding.

Conclusions:

• Coenzyme preference in ALDHs is mainly dictated by a single residue (position 195), allowing for evolutionary flexibility.
• This residue's nature influences electrostatic and steric interactions with the coenzyme's 2'-phosphate group.
• The adaptability of ALDH coenzyme preference suggests selection based on physiological requirements.