Diaminopimelic acid (DAP) is an amino acid. Unlike the 20 common amino acids found in human proteins, DAP’s presence is almost exclusively observed in bacteria and archaea, making it a unique molecular signature for these microorganisms. This selective occurrence highlights its importance to the survival and structural integrity of bacterial life forms.
Defining Diaminopimelic Acid
Diaminopimelic acid (DAP) is an amino acid structurally distinct from common amino acids. It is an epsilon-carboxy derivative of lysine, sharing a similar backbone but with an additional carboxyl group. DAP is a non-proteinogenic amino acid, meaning it is not typically incorporated into human proteins. Its primary significance lies in its nearly exclusive presence within bacterial and archaeal cell walls, serving as a distinctive biochemical marker. The meso-isomer of 2,6-diaminopimelic acid is the specific form that is a constituent of bacterial peptidoglycan.
Its Essential Role in Bacterial Cell Wall Structure
Diaminopimelic acid is a central component of peptidoglycan, the mesh-like layer forming the bacterial cell wall. Peptidoglycan provides structural integrity, safeguarding bacteria from osmotic lysis, which occurs when internal cellular pressure causes the cell to burst. This protective exoskeleton is important for bacterial growth and survival.
The peptidoglycan structure consists of alternating N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) sugar units. These strands are cross-linked by short peptide chains, creating a strong, net-like sacculus around the bacterial membrane. In many bacteria, particularly Gram-negative species and mycobacteria, DAP is located at the third position of these peptide side chains.
DAP’s unique structure, with its two amino groups, allows it to act as a cross-linking amino acid. It connects adjacent glycan strands by forming a peptide bond with a D-alanine residue from a neighboring peptide. Transpeptidases perform this cross-linking, forming a rigid, protective barrier around the bacterium. The degree and type of cross-linking, which often involve DAP, contribute significantly to the overall strength and shape of the bacterial cell wall.
Targeting Diaminopimelic Acid in Antibiotic Development
The unique presence of diaminopimelic acid in bacterial cell walls, and its absence in human cells, makes the enzymes involved in its synthesis or incorporation into peptidoglycan attractive targets for antibiotic development. This selective targeting allows for the design of drugs that can specifically harm bacteria without causing significant toxicity to human cells. The biosynthesis of DAP occurs through a specific pathway, and interfering with this pathway can compromise the integrity of the bacterial cell wall.
Several enzymes in the DAP biosynthetic pathway, such as meso-diaminopimelate dehydrogenase (m-Ddh) and DAP epimerase (DapF), are considered promising targets for novel antimicrobial agents. Antibiotics can work by inhibiting these enzymes, thereby preventing the bacteria from synthesizing sufficient DAP. A deficiency in DAP can lead to an inability to construct new cell wall peptidoglycan.
Interfering with DAP’s role in peptidoglycan synthesis weakens the bacterial cell wall, making the bacteria susceptible to osmotic lysis. For instance, some antibiotics, such as beta-lactams, inhibit transpeptidases, which are the enzymes responsible for forming the cross-links involving DAP in the cell wall. By disrupting these cross-links, the antibiotic compromises the structural integrity of the cell wall, ultimately leading to bacterial death. The ongoing threat of antibiotic resistance further emphasizes the importance of exploring and targeting unique bacterial components like DAP for new drug discovery.