# Dihydroneopterin aldolase

The enzyme dihydroneopterin aldolase (EC 4.1.2.25) catalyzes the chemical reaction
    2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8- dihydropteridine $\rightleftharpoons$ 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine + glycolaldehyde
This enzyme belongs to the family of lyases, specifically the aldehyde-lyases, which cleave carbon-carbon bonds. The systematic name of this enzyme class is 2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8-dihydropt eridine glycolaldehyde-lyase (2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine-forming). Other names in common use include 2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8-, and dihydropteridine glycolaldehyde-lyase. This enzyme participates in folate biosynthesis.

## Structural studies

The structural studies of DHNA have greatly advanced our understanding of its catalytic mechanism, revealing the roles of conserved amino acids in substrate binding and enzymatic activity. Comparative analyses of bacterial DHNA enzymes have uncovered differences in their active site architectures, providing valuable information for the design of species-specific inhibitors. These findings underscore the potential of targeting DHNA as a strategy to disrupt folate biosynthesis in pathogenic bacteria, as demonstrated by the successful inhibition of Staphylococcus aureus and Mycobacterium tuberculosis DHNA in vitro. The absence of DHNA in mammalian cells enhances the selectivity and therapeutic potential of DHNA-specific antimicrobial agents, reducing the likelihood of off-target effects.
Furthermore, the study of bifunctional DHNA-HPPK enzymes, such as those found in Streptococcus pneumoniae, has illuminated the interplay between folate pathway enzymes, offering additional targets for antimicrobial drug development. The development of potent DHNA inhibitors has been a promising step toward novel antibacterial therapies, with some compounds achieving nanomolar-level efficacy in vitro. However, the lack of structural data for Helicobacter pylori DHNA remains a significant gap, emphasizing the need for future research to facilitate the development of narrow-spectrum antibiotics tailored to specific infections.
Dihydroneopterin aldolase (DHNA, EC 4.1.2.25) plays a key role in turning 7,8-dihydro-d-neopterin (DHNP) into 6-hydroxymethyl-7,8-dihydropterin (HP), which is part of the folate biosynthesis process—an important focus for creating new antimicrobial drugs [1]. Folate cofactors are vital for all living organisms [2]. While most microorganisms can produce folates from scratch, mammals can't make them due to missing three enzymes in the middle of their folate pathway; instead, they rely on getting these nutrients through their diet. DHNA is one of those absent enzymes in mammals and stands out as a promising target for developing effective antimicrobial treatments [3].
The dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of the FolB protein plays a crucial role in transforming 7,8-dihydroneopterin (DHNP)into both 6-hydroxymethyl-7,8-dihydropterin (HP) and glycolaldehyde (GA) within the folate pathway. The FolB protein found in Mycobacterium tuberculosis (MtFolB) is vital for the survival of these bacteria and stands out as a significant target for drug development efforts.
Researcher synthesized various S8-functionalized derivatives of 8-mercaptoguanine to test their effectiveness against MtFolB, finding that these compounds had IC50 values falling within the submicromolar range—pretty impressive! They also figured out how well some of the strongest inhibitors worked by determining their inhibition constants and modes.
Moreover, they conducted molecular docking studies to explore how these enzymes interact with inhibitors and what conformations ligands take on during this process. As far as we know, this research marks the first discovery of a new class of MtFolB inhibitors!

## Structural studies

As of late 2007, 13 structures have been solved for this class of enzymes, with PDB accession codes 1NBU, 1RRI, 1RRW, 1RRY, 1RS2, 1RS4, 1RSD, 1RSI, 1U68, 1Z9W, 2CG8, 2NM2, and 2NM3.