Adenylosuccinate lyase

Source: Wikipedia, the free encyclopedia.
ADSL
Available structures
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000239900

ENSMUSG00000022407

UniProt

P30566

P54822

RefSeq (mRNA)

NM_000026
NM_001123378
NM_001317923
NM_001363840

NM_009634

RefSeq (protein)

NP_000017
NP_001116850
NP_001304852
NP_001350769

NP_033764

Location (UCSC)Chr 22: 40.35 – 40.39 MbChr 15: 80.83 – 80.86 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Adenylosuccinate lyase
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

Adenylosuccinate lyase (or adenylosuccinase) is an enzyme that in humans is encoded by the ADSL gene.[6]

Adenylosuccinate lyase converts

SAICAR into AICAR
and fumarate.

Adenylosuccinate lyase is part of the

homotetramer with three domains in each monomer and four active sites
per homotetramer.

enzymatic activity cause clinical symptoms that mark the condition adenylosuccinate lyase deficiency
.

This protein may use the morpheein model of allosteric regulation.[7]

Function

This flow chart shows the steps in the biosynthesis of AMP.Steps in green show steps catalyzed by ASL Steps in red show the dephosphorylation of ASL's substrates

Adenylosuccinate lyase (ASL) is an enzyme that catalyzes two reactions in the

cellular replication, but also because it helps regulate metabolic processes by controlling the levels of AMP and fumarate in the cell.[9]

ASL cleaves SAICAR into AICAR and fumarate, and adenylosuccinate into AMP and fumarate. This figure was inspired by one from a paper by Toth and Yeates.[5]

Structure

Subunits

Adenylosuccinate lyase belongs to the β-elimination superfamily, and as such its structure is a homotetramer . The monomer of adenylosuccinate lyase has three domains. In

dihedral symmetry. The tetramer has four active sites, each where three domains meet.[5]

Adenylosuccinate lyase in humans and Bacillus subtilis can be competitively inhibited by the substrate analog adenosine phosphonobutyric acid 2’(3’), 5’-diphosphate (APBADP). APBADP is a competitive inhibitor for both of the reactions catalyzed by adenylosuccinate lyase, and kinetic studies with APBADP show that the substrates for both reactions use the same active site.[10] In the ASL-catalyzed reaction splitting adenylosuccinate into adenosine monophosphate (AMP) and fumarate, the AMP must rotate slightly after the reaction is complete and before fumarate is released in order for both products to fit in the active site.[11]

Mutations

Adenylosuccinate lyase

mutants can have considerably reduced activity whether the mutation is in or away from the active site. Disease-causing ASL mutants R396C and R396H are at the entrance to the active site and have lower Vmax than the wild-type ASL, but the mutants K246E and L311V which are away from the active site also cause decreased Vmax. ASL mutant R194C is away from the active site, and though it maintains a Vmax similar to wild-type ASL, it was shown to be the least conformationally stable of the five mutants in vitro and still causes disease.[12]

Mechanism

It was previously thought that the mechanism of action for adenylosuccinate lyase was a concerted catalysis where the hydrogen on the β-carbon (with respect to the leaving nitrogen) was abstracted by the catalytic base at the same time that the leaving nitrogen was protonated by the catalytic acid for E2 elimination.

resonance stabilization of the carbanion occurs, and lastly the protonation of the leaving nitrogen which causes the C-N bond to break.[9] Experimental confirmation of the deprotonation, carbanion formation, and the rate-limiting step of protonation causing cleavage means this is an E1cb mechanism. The most recent data suggest that the catalytic acid is His171, which was previously thought to be the catalytic base, and that somewhat unusually it is a serine at position 295 acts as the catalytic base. The cleavage of adenylosuccinate to AMP and fumarate is an ordered uni-bi mechanism, which means that after cleavage the fumarate leaves the active site before the AMP does.[13]

ASL's mechanism of action. First the acid deprotonates the β-carbon, then a carbanion forms and is resonance stabilized, lastly nitrogen accepts a proton and the C-N bond is cleaved.This figure was inspired by a paper by Tsai et al.[9] NOTE: the fumarate structure in this figure is wrong. There must be a double bond, in trans configuration, between carbon atoms 2 and 3.

Role in disease

Mutated adenylosuccinate lyase (ASL) causes clinical disease in patients that is referred to as

homozygous develop clinical disease.[16] The number of disease-causing genotypes keeps increasing as more mutations are discovered, and now thirty different point mutations have been identified so far, and one deletion, that cause adenylosuccinate lyase deficiency.[17]

When the substrates of ASL (adenylosuccinate and SAICAR) build up due to enzyme deficiency, they are dephosphorylated and turn into succinyladenosine (S-Ado) and succinylaminoimidazole carboximide riboside (SAICA riboside).[18] Normally these compounds are not present in the cerebrospinal fluid or urine because ASL acts on the majority of the substrate molecules before they can build up and be phosphorylated.[15] In the past there has not been a good test for adenylosuccinate lyase deficiency, making the rare disease difficult to diagnose, but recently a test was developed to detect SAICA and S-Ado in the urine. The test is inexpensive and had no false positives or false negatives in the researchers’ small sample.[19]

It is thought that SAICA riboside may be the more toxic compound as it is found at higher levels in patients with severe clinical symptoms, and some researchers think S-Ado may even be protective. More research needs to be done on what determines disease severity, but the instability of human ASL in the lab setting has been an obstacle to this research.[17]

Therapeutic applications

As resistance to anti-malarials increases, researchers are looking for new strategies to target the Plasmodium parasites which cause

P. falciparum. Some researchers suggested that ASL be looked into as a potential drug target because though interruption of the de novo purine biosynthesis pathway is toxic to the host, Plasmodium ASL has a low level of sequence homology with human ASL which may make any anti-Plasmodium ASL drugs specific enough not to harm human hosts.[20]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000239900 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022407 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^
    PMID 10673438
    .
  6. ^ "Entrez Gene: Adenylosuccinate lyase". Retrieved 2012-03-01.
  7. PMID 22182754
    .
  8. PMID 16839792
    .
  9. ^
    PMID 17531264
    .
  10. PMID 18469177
    .
  11. PMID 19724117
    .
  12. PMID 19405474
    .
  13. PMID 19111634
    .
  14. S2CID 52833816
    .
  15. ^
    PMID 16973378
    .
  16. S2CID 21577926
    .
  17. ^
    PMID 12876319
    .
  18. S2CID 54275991
    .
  19. S2CID 1534130
    .
  20. PMID 9274883
    .

Further reading

External links
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