Lysine Biosynthesis Pathway Biochemistry

The lysine biosynthetic pathway in bacteria, plants and certain algae proceeds via the diaminopimelate (DAP) route, a multi‐step process converting aspartate to the essential amino acid lysine. The first committed reaction is catalysed by dihydrodipicolinate synthase (DHDPS), which condenses pyruvate with l-aspartate-β-semialdehyde to form dihydrodipicolinate. This intermediate is then reduced by dihydrodipicolinate reductase (DHDPR) to yield tetrahydrodipicolinate. Subsequent steps involve transamination and either succinylation or acetylation routes to produce meso-diaminopimelate, which is finally decarboxylated by diaminopimelate decarboxylase (DAPDC) to release l-lysine. Each enzyme exhibits distinctive quaternary assembly and regulatory features, with DHDPS subject to feedback inhibition by lysine in many species, while DHDPR and DAPDC display varied oligomeric states that influence catalytic turnover. Beyond fundamental metabolism, this pathway is targeted for herbicide and antibiotic development, as well as crop biofortification, given lysine’s role as a limiting amino acid in cereals. Structural insights and mechanistic studies continue to reveal allosteric sites and protein-protein interactions that underpin enzyme function and pave the way for applied interventions.

Research from Nature Portfolio

Repurposing of a historical antibiotic scaffold has led to the identification of inhibitors targeting plant and bacterial DHDPR. The lead compound exhibits selective activity against weed species without affecting mammalian cells, and analogue optimisation has broadened its spectrum to both monocot and dicot weeds. Structural and biochemical analyses confirm active site engagement and potent in vitro inhibition, demonstrating proof-of-concept for herbicidal modes of action. Structural and functional characterisation of DHDPS and DHDPR from cyanobacteria has elucidated canonical bacterial tetrameric architectures, offering an evolutionary link between bacterial and plant forms. High-resolution crystal structures revealed conserved active site geometries and oligomerisation interfaces, informing hypotheses on the divergence of quaternary arrangements. In the context of tuberculosis, detailed enzymology and crystallography of Mycobacterium tuberculosis DHDPS with α-ketopimelic acid analogues have defined key active site interactions and competitive inhibition profiles. Molecular dynamics simulations highlighted differences in ligand stability and enzyme dynamics, underpinning novel antimicrobial strategies aimed at crippled lysine biosynthesis in the pathogen.

Lysine Biosynthesis Pathway Biochemistry publication trend

The graph below shows the total number of articles in lysine biosynthesis pathway biochemistry across all publications each year (not limited to Nature Index journals).

Technical terms

Dihydrodipicolinate synthase (DHDPS): Enzyme catalysing the first committed condensation step in lysine biosynthesis.

Dihydrodipicolinate reductase (DHDPR): NAD(P)H-dependent enzyme reducing dihydrodipicolinate to tetrahydrodipicolinate.

Diaminopimelate decarboxylase (DAPDC): Pyridoxal 5′-phosphate-dependent enzyme catalysing the final decarboxylation to produce l-lysine.

Diaminopimelate (DAP): Key intermediate in the lysine biosynthetic pathway linking reduction and decarboxylation steps.

Quaternary structure: Assembly of multiple protein subunits that influences enzyme regulation and stability.

Allosteric inhibition: Regulation of enzyme activity through effector binding at sites distinct from the active site.

References

1. Repurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activity. Communications Biology (2023).
2. Towards novel herbicide modes of action by inhibiting lysine biosynthesis in plants. eLife (2021).
3. Dimerization of Bacterial Diaminopimelate Decarboxylase Is Essential for Catalysis*. Journal of Biological Chemistry (2016).
4. Structure and Function of Cyanobacterial DHDPS and DHDPR. Scientific Reports (2016).
5. Inhibition of Mycobacterium tuberculosis dihydrodipicolinate synthase by alpha-ketopimelic acid and its other structural analogues. Scientific Reports (2016).
6. Characterisation of the First Enzymes Committed to Lysine Biosynthesis in Arabidopsis thaliana. PLOS ONE (2012).