DERA

DERA is a class I deoxyribose-5-phosphate aldolase that cleaves 2-deoxy-D-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde via a Schiff base intermediate formed at an active-site lysine, channelling deoxyribose into glycolysis (PMID:6749498, PMID:9226884). Catalytic efficiency depends on anti-correlated protein dynamics coupled through non-canonical phosphate-binding residues (Ser238/Ser239) and on an intrinsically disordered C-terminal tail whose terminal tyrosine (Y259) samples open and closed conformations to position itself for proton abstraction in the active site (PMID:29910900, PMID:30101036). In human cells, DERA interacts with YBX1 and is recruited to stress granules under oxidative or mitochondrial stress, where it promotes stress granule formation and cell survival; DERA also enables ATP production from extracellular deoxynucleosides when mitochondrial function is impaired (PMID:25229427). The enzyme is subject to covalent inactivation by crotonaldehyde at active-site residue C47, a vulnerability that can be abolished by mutagenesis without loss of stereoselectivity (PMID:28347769).

1. 1982 High

   Identification of DERA as a class I aldolase using a Schiff base mechanism with an active-site lysine established the fundamental catalytic strategy of the enzyme.

   Evidence Protein purification, amino acid sequencing, and catalytic activity assays on the E. coli deoC gene product

   PMID:6749498

   Open questions at the time

   • Identity of the specific lysine residue was tentative
   • Oligomeric state relevance to activity was not resolved
   • No structural model of the active site was available
2. 1997 Medium

   Demonstration that DERA activity is conserved across vertebrate tissues and cell lines established its physiological role in channelling deoxyribose-5-phosphate from nucleoside catabolism into central carbon metabolism.

   Evidence Enzyme activity assays in vertebrate liver extracts and multiple mammalian cell lines

   PMID:9226884

   Open questions at the time

   • No genetic loss-of-function validation in mammalian systems
   • Metabolic flux through the DERA pathway was not quantified
   • Regulation of DERA expression in different tissues was not addressed
3. 2014 High

   Discovery that human DERA interacts with YBX1, localizes to stress granules under oxidative/mitochondrial stress, and supports ATP production from deoxynucleosides revealed an unexpected cell-protective role beyond housekeeping metabolism.

   Evidence Co-immunoprecipitation with YBX1, shRNA knockdown with stress granule and apoptosis readouts, ATP measurements in mitochondrially compromised cells

   PMID:25229427

   Open questions at the time

   • Mechanism of DERA recruitment to stress granules is unknown
   • Whether enzymatic activity is required for the stress granule phenotype was not tested
   • The YBX1 interaction interface is uncharacterized
4. 2015 High

   Establishing that non-canonical phosphate-binding residues Ser238/Ser239 transmit anti-correlated motions coupled to catalytic efficiency revealed how distal dynamics contribute to the retro-aldol reaction.

   Evidence Site-directed and site-saturation mutagenesis, kinetic analysis, and molecular dynamics simulations of DERA

   PMID:29910900

   Open questions at the time

   • Coupling between dynamics and catalysis was inferred computationally and from temperature-dependence, not directly measured structurally
   • Contribution of these residues in the human enzyme was not confirmed
   • Role of dynamics in the forward aldol direction was not examined
5. 2017 High

   Identification of C47 as the site of covalent inactivation by crotonaldehyde explained the long-standing vulnerability of DERA to its own product-derived inhibitor and demonstrated that mutagenesis can decouple inactivation from catalysis.

   Evidence Site-directed mutagenesis of C47 with activity and inhibition kinetics

   PMID:28347769

   Open questions at the time

   • A C47-independent inactivation pathway was noted but not characterized
   • Structural basis of the Michael adduct was not solved crystallographically
   • Relevance of C47 inactivation to in vivo regulation is unknown
6. 2018 High

   NMR characterization of the intrinsically disordered C-terminal tail showed that Y259 samples open/closed states and enters the active site for proton abstraction, resolving how a flexible element controls catalytic turnover.

   Evidence NMR spectroscopy (NOE, H/D exchange, phosphate titration) and molecular dynamics on E. coli DERA

   PMID:30101036

   Open questions at the time

   • Whether the human C-terminal tail exhibits the same conformational dynamics is untested
   • Kinetic contribution of the open–closed equilibrium to overall rate was not quantified
   • No crystal structure of the closed conformation was obtained
7. 2020 High

   Systematic active-site mutagenesis showed that donor specificity (acetaldehyde vs. glyceraldehyde-3-phosphate) can be engineered independently, and revealed a previously unrecognized native formaldehyde addition activity.

   Evidence Site-directed mutagenesis of 24 active-site positions with substrate activity assays and machine-learning guided design

   PMID:33147349

   Open questions at the time

   • Physiological relevance of formaldehyde donor activity is unknown
   • Structural basis for the altered donor specificity was not determined
   • In vivo metabolic consequences of altered specificity were not tested

• Key unresolved questions include the structural basis for DERA recruitment to stress granules, whether enzymatic activity is required for the stress-protective phenotype, and the physiological significance of DERA's catalytic promiscuity in human cells.
• No separation-of-function mutant distinguishing catalytic and stress granule roles
• Human DERA crystal structure with C-terminal tail resolved is lacking
• In vivo metabolic flux through the DERA pathway in human tissues has not been measured