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.[2] Comparative analyses of bacterial DHNA enzymes have uncovered differences in their active site architectures, providing valuable information for the design of species-specific inhibitors.[3] 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.[4] 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.[5]
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.[6] The development of potent DHNA inhibitors has been a promising step toward novel antibacterial therapies, with some compounds achieving nanomolar-level efficacy in vitro.[4] 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.[4]
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![7]
Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. The versatility of PLP arises from its ability to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.
GTP cyclohydrolase I (GTPCH) (EC 3.5.4.16) is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate (GTP) to form 7,8-dihydroneopterin triphosphate (7,8-DHNP-3'-TP, 7,8-NH2-3'-TP).
Amino acid biosynthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids.
Dihydropteroate synthase (DHPS) is an enzyme classified under EC 2.5.1.15. It produces dihydropteroate in bacteria, but it is not expressed in most eukaryotes including humans. This makes it a useful target for sulfonamide antibiotics, which compete with the PABA precursor.
Serine hydroxymethyltransferase (SHMT) is a pyridoxal phosphate (PLP) (Vitamin B6) dependent enzyme (EC 2.1.2.1) which plays an important role in cellular one-carbon pathways by catalyzing the reversible, simultaneous conversions of L-serine to glycine and tetrahydrofolate (THF) to 5,10-methylenetetrahydrofolate (5,10-CH2-THF). This reaction provides the largest part of the one-carbon units available to the cell.
Sepiapterin reductase is an enzyme that in humans is encoded by the SPR gene.
Cystathionine beta-lyase, also commonly referred to as CBL or β-cystathionase, is an enzyme that primarily catalyzes the following α,β-elimination reaction
The enzyme L-erythro-3-hydroxyaspartate aldolase catalyzes the chemical reaction
The enzyme diaminopimelate decarboxylase (EC 4.1.1.20) catalyzes the cleavage of carbon-carbon bonds in meso-2,6-diaminoheptanedioate (diaminopimelate) to produce CO2 and L-lysine, the essential amino acid. It employs the cofactor pyridoxal phosphate, also known as PLP, which participates in numerous enzymatic transamination, decarboxylation and deamination reactions.
Isocitrate lyase, or ICL, is an enzyme in the glyoxylate cycle that catalyzes the cleavage of isocitrate to succinate and glyoxylate. Together with malate synthase, it bypasses the two decarboxylation steps of the tricarboxylic acid cycle and is used by bacteria, fungi, and plants.
In enzymology, an aminodeoxychorismate synthase is an enzyme that catalyzes the chemical reaction
In enzymology, a dihydrofolate synthase is an enzyme that catalyzes the chemical reaction
The enzyme 3-dehydroquinate dehydratase (EC 4.2.1.10) catalyzes the chemical reaction
The enzyme imidazoleglycerol-phosphate dehydratase (EC 4.2.1.19) catalyzes the chemical reaction
In enzymology, a 2-isopropylmalate synthase (EC 2.3.3.13) is an enzyme that catalyzes the chemical reaction
In enzymology, a 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase is an enzyme that catalyzes the chemical reaction
2-Amino-4-hydroxy-6-pyrophosphoryl-methylpteridine is a pteridine; a precursor to dihydrofolic acid.
7,8-Dihydroneopterin triphosphate (DHNTP) is an intermediate in tetrahydrobiopterin biosynthesis. It is transformed by 6-pyruvoyltetrahydropterin synthase into 6-pyruvoyl-tetrahydropterin. It is also used in the Queuosine/Archeosine Pathway.
3-Deoxy-D-arabinoheptulosonate 7-phosphate (DAHP) synthase is the first enzyme in a series of metabolic reactions known as the shikimate pathway, which is responsible for the biosynthesis of the amino acids phenylalanine, tyrosine, and tryptophan. Since it is the first enzyme in the shikimate pathway, it controls the amount of carbon entering the pathway. Enzyme inhibition is the primary method of regulating the amount of carbon entering the pathway. Forms of this enzyme differ between organisms, but can be considered DAHP synthase based upon the reaction that is catalyzed by this enzyme.
7,8-didemethyl-8-hydroxy-5-deazariboflavin synthase (EC 4.3.1.32, FO synthase) and 5-amino-6-(D-ribitylamino)uracil—L-tyrosine 4-hydroxyphenyl transferase (EC 2.5.1.147) are two enzymes always complexed together to achieve synthesis of FO, a precursor to Coenzyme F420. Their systematic names are 5-amino-5-(4-hydroxybenzyl)-6-(D-ribitylimino)-5,6-dihydrouracil ammonia-lyase (7,8-didemethyl-8-hydroxy-5-deazariboflavin-forming) and 5-amino-6-(D-ribitylamino)uracil:L-tyrosine, 4-hydroxyphenyl transferase respectively. The enzymes catalyse the following chemical reactions:
1 2 3 Li, James J.; Chao, Hann-Guang; Wang, Haixia; Tino, Joseph A.; Lawrence, R. Michael; Ewing, William R.; Ma, Zhengping; Yan, Mujing; Slusarchyk, Dorothy; Seethala, Ramakrishna; Sun, Huabin; Li, Danshi; Burford, Neil T.; Stoffel, Robert H.; Salyan, Mary Ellen (2004-03-25). "Discovery of a potent and novel motilin agonist". Journal of Medicinal Chemistry. 47 (7): 1704–1708. doi:10.1021/jm0304865. ISSN0022-2623. PMID15027861.
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