The

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

diaminopimelate decarboxylase () catalyzes the cleavage of carbon-carbon bonds in meso 2,6 diaminoheptanedioate to produce CO₂ and L-lysine, the essential amino acid. It employs the cofactor

pyridoxal phosphate 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 a ...

, also known as PLP, which participates in numerous enzymatic

transamination Transamination is a chemical reaction that transfers an amino group to a ketoacid to form new amino acids. This pathway is responsible for the deamination of most amino acids. This is one of the major degradation pathways which convert essential ...

, decarboxylation and

deamination Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases. In the human body, deamination takes place primarily in the liver, however it can also occur in the kidney. In situations of ...

reactions. This enzyme belongs to the family of lyases, specifically the carboxy-lyases, which cleave carbon-carbon bonds. The

systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature. A semisystematic name or semitrivial ...

of this enzyme class is ''meso''-2,6-diaminoheptanedioate carboxy-lyase (L-lysine-forming).DAP-decarboxylase catalyzes the final step in the meso-diaminopimelate/lysine biosynthetic pathway. Lysine is used for protein synthesis and used in the

peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ba ...

layer of

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

bacteria cell walls. This enzyme is not found in humans, but the ortholog is

ornithine decarboxylase The enzyme ornithine decarboxylase (, ODC) catalyzes the decarboxylation of ornithine (a product of the urea cycle) to form putrescine. This reaction is the committed step in polyamine synthesis. In humans, this protein has 461 amino acids a ...

Structure

DAPDC is a PLP-dependent enzyme belonging to the

alanine racemase In enzymology, an alanine racemase () is an enzyme that catalyzes the chemical reaction :L-alanine \rightleftharpoons D-alanine Hence, this enzyme has one substrate, L-alanine, and one product, D-alanine. This enzyme belongs to the family o ...

family. This enzyme is generally dimeric with each monomer containing two domains. The first domain is the N-terminal α/β-barrel that binds the PLP to the active site lysine residue. The second domain is the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

β-sandwich. The active site is formed from residues present in both domains resulting in two active sites within the dimer. DAPDC_Active_Site

DAPDC is stereochemically specific due to the opposing chiralities at each terminus of diaminopimelate. In order for the L-lysine to be generated over D-lysine, decarboxylation must occur at the D-terminus. Whether DAPDC recognizes the terminus or not is dependent on the formation of a

Schiff base In organic chemistry, a Schiff base (named after Hugo Schiff) is a compound with the general structure ( = alkyl or aryl, but not hydrogen). They can be considered a sub-class of imines, being either secondary ketimines or secondary aldimine ...

with PLP. While the majority of DAPDC found in various species of bacteria have the same basic components, not all species follow the same structure. Some species of bacteria, such as Mycobacterium tuberculosis have been observed as a

tetramer A tetramer () ('' tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula ...

. The tetramer is shaped like a ring with the active sites accessible from the inside of the enzyme.

Mechanism

The first step in the mechanism is the same as for all type III PLP-dependent enzymes; the formation of a Schiff base with the substrate

amino group In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...

. The lysine residue binding PLP to the structure is replaced by diaminopimelate. DAPDC then uses the interaction of 3 residues ( Arginine, Aspartate, and Glutamate) within the active site to identify the D-stereocenter. The DAP is decarboxylated and then stabilized by PLP. It is not clear which general acid protonates after decarboxylation, but there is speculation that the lysine residue is the donor.

Regulation

DAPDC is regulated by the product L-lysine at relatively high concentrations. Compounds that are similar to DAP in chemical complexity do not inhibit the reaction, possibly due to the residue rulers creating specific bond angles. Diamines have a stronger inhibitory effect compared to dicarboxylic acids, most likely from interactions with PLP.

Function

Given that there are three pathways to convert aspartate to lysine, this is clearly an essential process for the cell, particularly in building cell walls in Gram-positive bacteria. There is no process for producing lysine in humans, but ornithine decarboxylase shares many similarities with DAPDC. Both enzymes use PLP as a cofactor and have similar structures forming the active sites. However, DAPDC differs in that it decarboxylates at the D-stereocenter and is highly stereospecific. These unique features make DAPDC a good candidate for antibacterial studies because potential inhibitors of such an integral step in cell viability would be unlikely to interact with necessary processes within humans.

Structure

Mechanism

Regulation

Function

References

Further reading