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CATH domain | Related DB codes (homologues) |
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3.20.20.70 : TIM Barrel | S00215,S00217,S00218,S00219,S00532,S00198,S00220,S00745,S00537,S00538,S00539,S00826,S00841,S00235,S00239,S00240,S00243,S00244,S00199,S00201,S00221,S00222,S00847,S00224,S00225,S00226,D00014,D00029,M00141,T00015,T00239,D00664,D00665,D00804,D00863,T00089 |
Enzyme Name | UniProtKB | KEGG |
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| P0A6L4 | P44539 |
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Protein name | N-acetylneuraminate lyase | N-acetylneuraminate lyase | N-acetylneuraminate lyaseN-acetylneuraminic acid aldolaseacetylneuraminate lyasesialic aldolasesialic acid aldolasesialate lyaseN-acetylneuraminic aldolaseneuraminic aldolaseN-acetylneuraminate aldolaseneuraminic acid aldolaseN-acetylneuraminic acid aldolaseneuraminate aldolaseN-acetylneuraminic lyaseN-acetylneuraminic acid lyaseNPLNALaseNANA lyaseacetylneuraminate pyruvate-lyaseN-acetylneuraminate pyruvate-lyase |
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Synonyms | EC 4.1.3.3N-acetylneuraminic acid aldolaseN-acetylneuraminate pyruvate-lyaseSialic acid lyaseSialate lyaseSialic acid aldolaseNALase | EC 4.1.3.3N-acetylneuraminic acid aldolaseN-acetylneuraminate pyruvate-lyaseSialic acid lyaseSialate lyaseSialic acid aldolase |
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RefSeq | NP_417692.1 (Protein) NC_000913.2 (DNA/RNA sequence) YP_491409.1 (Protein) NC_007779.1 (DNA/RNA sequence)
| NP_438311.1 (Protein) NC_000907.1 (DNA/RNA sequence)
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Pfam | PF00701 (DHDPS) [Graphical view]
| PF00701 (DHDPS) [Graphical view]
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KEGG pathways | MAP code | Pathways |
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MAP00530 | Aminosugars metabolism |
UniProtKB:Accession Number | P0A6L4 | P44539 |
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Entry name | NANA_ECOLI | NANA_HAEIN |
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Activity | N-acetylneuraminate = N-acetyl-D-mannosamine + pyruvate. | N-acetylneuraminate = N-acetyl-D-mannosamine + pyruvate. |
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Subunit | Homotetramer. | Homotetramer. |
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Subcellular location | Cytoplasm. | Cytoplasm. |
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Cofactor |
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Compound table: links to PDB-related databases & PoSSuM |
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| Substrates | Products | intermediates |
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KEGG-id | C00270 | C00645 | C00022 |
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Compound | N-Acetylneuraminate | N-Acetyl-D-mannosamine | Pyruvate | Schiff-base with substrate | Schiff-base with product |
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Type | amide group,carbohydrate,carboxyl group | amide group,carbohydrate | carbohydrate,carboxyl group |
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ChEBI | 17012
| 63153
| 32816
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PubChem | 439197
| 439281
| 1060
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| | | | | | | | | | | | |
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1f5zA |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1f5zB |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1f5zC |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1f5zD |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1f6kA |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1f6kC |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1f6pA |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1f6pB |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1f6pC |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1f6pD |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1f73A |  |  |  |  |  |  |  | Analogue:HMN | Unbound | Unbound | Unbound | Unbound |
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1f73B |  |  |  |  |  |  |  | Analogue:HMN | Unbound | Unbound | Unbound | Unbound |
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1f73C |  |  |  |  |  |  |  | Analogue:HMN | Unbound | Unbound | Unbound | Unbound |
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1f73D |  |  |  |  |  |  |  | Analogue:HMN | Unbound | Unbound | Unbound | Unbound |
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1f74A |  |  |  |  |  |  |  | Analogue:NAY | Unbound | Unbound | Unbound | Unbound |
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1f74C |  |  |  |  |  |  |  | Analogue:NAY | Unbound | Unbound | Unbound | Unbound |
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1f7bA |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Intermediate-analogue:NAU | Unbound |
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1f7bC |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Intermediate-analogue:NAV | Unbound |
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1fdyA |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Intermediate-analogue:3PY |
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1fdyB |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Intermediate-analogue:3PY |
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1fdyC |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Intermediate-analogue:3PY |
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1fdyD |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Intermediate-analogue:3PY |
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1fdzA |  |  |  |  |  |  |  | Unbound | Unbound | Bound:PYR | Unbound | Intermediate-bound:PYR |
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1fdzB |  |  |  |  |  |  |  | Unbound | Unbound | Bound:PYR | Unbound | Intermediate-bound:PYR |
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1fdzC |  |  |  |  |  |  |  | Unbound | Unbound | Bound:PYR | Unbound | Intermediate-bound:PYR |
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1fdzD |  |  |  |  |  |  |  | Unbound | Unbound | Bound:PYR | Unbound | Intermediate-bound:PYR |
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1nal1 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1nal2 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1nal3 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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1nal4 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound | Unbound |
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References for Catalytic Mechanism | References | Sections | No. of steps in catalysis |
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[6] |
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| [9] | Fig.1(a), Fig.6, p.394-395 |
| [11] |
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| [13] | Fig.9, p.416-418 | 9 |
references | [1] |
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PubMed ID | 6301475 |
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Journal | Biochem Biophys Res Commun |
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Year | 1983 |
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Volume | 111 |
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Pages | 668-74 |
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Authors | Deijl CM, Vliegenthart JF |
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Title | Configuration of substrate and products of N-acetylneuraminate pyruvate-lyase from Clostridium perfringens. |
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[2] |
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PubMed ID | 3024643 |
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Journal | Biochem Int |
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Year | 1986 |
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Volume | 13 |
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Pages | 493-500 |
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Authors | Kolisis FN, Hervagault JF |
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Title | Theoretical and experimental study on the competition of NANA-aldolase and cytidine-5'-monophosphosialate-synthase for their common substrate N-acetylneuraminic acid. |
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[3] |
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PubMed ID | 2896604 |
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Journal | FEBS Lett |
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Year | 1988 |
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Volume | 232 |
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Pages | 145-7 |
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Authors | Gross HJ, Brossmer R |
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Title | Inhibition of N-acetylneuraminate lyase by N-acetyl-4-oxo-D-neuraminic acid. |
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[4] |
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PubMed ID | 2896358 |
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Journal | Prog Clin Biol Res |
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Year | 1988 |
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Volume | 259 |
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Pages | 413-20 |
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Authors | Kolisis FN, Evangelopoulos AE |
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Title | Studies on metabolic regulation and estimation of sialic acids by enzyme immobilization techniques. |
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[5] |
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Comments | X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS). |
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Medline ID | 94363237 |
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PubMed ID | 8081752 |
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Journal | Structure |
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Year | 1994 |
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Volume | 2 |
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Pages | 361-9 |
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Authors | Izard T, Lawrence MC, Malby RL, Lilley GG, Colman PM |
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Title | The three-dimensional structure of N-acetylneuraminate lyase from Escherichia coli. |
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Related PDB | 1nal |
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Related UniProtKB | P0A6L4 |
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[6] |
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Journal | J Org Chem |
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Year | 1995 |
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Volume | 60 |
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Pages | 3663-70 |
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Authors | Fitz W, Schwark JR, Wong CH |
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Title | Aldotetroses and C(3)-modified aldohexoses as substrates for N-acetylneuraminic acid aldolase: a model for the explanation of the normal and the inversed stereoselectivity. |
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[7] |
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PubMed ID | 8581891 |
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Journal | Carbohydr Res |
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Year | 1996 |
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Volume | 280 |
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Pages | 101-10 |
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Authors | Murakami M, Ikeda K, Achiwa K |
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Title | Chemoenzymatic synthesis of neuraminic acid analogs structurally varied at C-5 and C-9 as potential inhibitors of the sialidase from influenza virus. |
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[8] |
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PubMed ID | 8704962 |
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Journal | Microbiology |
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Year | 1996 |
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Volume | 142 |
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Pages | 1221-30 |
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Authors | Homer KA, Kelley S, Hawkes J, Beighton D, Grootveld MC |
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Title | Metabolism of glycoprotein-derived sialic acid and N-acetylglucosamine by Streptococcus oralis. |
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[9] |
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Comments | X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) OF COMPLEXES WITH HYDROXYPYRUVATE AND PYRUVATE. |
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Medline ID | 97199395 |
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PubMed ID | 9047371 |
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Journal | J Mol Biol |
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Year | 1997 |
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Volume | 266 |
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Pages | 381-99 |
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Authors | Lawrence MC, Barbosa JA, Smith BJ, Hall NE, Pilling PA, Ooi HC, Marcuccio SM |
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Title | Structure and mechanism of a sub-family of enzymes related to N-acetylneuraminate lyase. |
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Related PDB | 1fdy,1fdz |
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Related UniProtKB | P0A6L4 |
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[10] |
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PubMed ID | 9535696 |
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Journal | Protein Expr Purif |
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Year | 1998 |
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Volume | 12 |
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Pages | 295-304 |
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Authors | Lilley GG, Barbosa JA, Pearce LA |
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Title | Expression in Escherichia coli of the putative N-acetylneuraminate lyase gene (nanA) from Haemophilus influenzae: overproduction, purification, and crystallization. |
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[11] |
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PubMed ID | 11674166 |
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Journal | J Org Chem |
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Year | 1999 |
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Volume | 64 |
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Pages | 945-49 |
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Authors | Smith BJ, Lawrence MC, Barbosa JA |
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Title | Substrate-Assisted Catalysis in Sialic Acid Aldolase. |
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[12] |
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PubMed ID | 10732983 |
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Journal | Bioorg Med Chem |
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Year | 2000 |
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Volume | 8 |
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Pages | 657-64 |
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Authors | Kiefelt MJ, Wilson JC, Bennett S, Gredley M, von Itzstein M |
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Title | Synthesis and evaluation of C-9 modified N-acetylneuraminic acid derivatives as substrates for N-acetylneuraminic acid aldolase. |
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[13] |
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Comments | X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF NATIVE PROTEIN AND COMPLEXES WITH SIALIC ACID ALDITOL; 4-DEOXY-SIALIC ACID AND 4-OXO-SIALIC ACID. |
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Medline ID | 20487594 |
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PubMed ID | 11031117 |
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Journal | J Mol Biol |
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Year | 2000 |
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Volume | 303 |
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Pages | 405-21 |
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Authors | Barbosa JA, Smith BJ, DeGori R, Ooi HC, Marcuccio SM, Campi EM, Jackson WR, Brossmer R, Sommer M, Lawrence MC |
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Title | Active site modulation in the N-acetylneuraminate lyase sub-family as revealed by the structure of the inhibitor-complexed Haemophilus influenzae enzyme. |
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Related PDB | 1f5z,1f6k,1f6p,1f73,1f74,1f7b |
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Related UniProtKB | P44539 |
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[14] |
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PubMed ID | 11434370 |
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Journal | Carbohydr Res |
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Year | 2001 |
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Volume | 332 |
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Pages | 133-9 |
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Authors | Kok GB, Campbell M, Mackey BL, von Itzstein M |
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Title | Synthesis of C-3 nitrogen-containing derivatives of N-acetyl-alpha,beta-D-mannosamine as substrates for N-acetylneuraminic acid aldolase. |
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[15] |
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PubMed ID | 11504613 |
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Journal | Trends Biochem Sci |
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Year | 2001 |
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Volume | 26 |
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Pages | 468-9 |
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Authors | Baardsnes J, Davies PL |
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Title | Sialic acid synthase: the origin of fish type III antifreeze protein? |
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[16] |
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PubMed ID | 12083785 |
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Journal | Biochem Biophys Res Commun |
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Year | 2002 |
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Volume | 295 |
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Pages | 167-73 |
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Authors | Hwang TS, Hung CH, Teo CF, Chen GT, Chang LS, Chen SF, Chen YJ, Lin CH |
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Title | Structural characterization of Escherichia coli sialic acid synthase. |
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[17] |
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PubMed ID | 12453637 |
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Journal | Biochimie |
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Year | 2002 |
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Volume | 84 |
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Pages | 655-60 |
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Authors | Bulai T, Bratosin D, Artenie V, Montreuil J |
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Title | Characterization of a sialate pyruvate-lyase in the cytosol of human erythrocytes. |
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[18] |
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PubMed ID | 12150863 |
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Journal | Bioorg Med Chem |
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Year | 2002 |
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Volume | 10 |
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Pages | 3175-85 |
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Authors | Humphrey AJ, Fremann C, Critchley P, Malykh Y, Schauer R, Bugg TD |
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Title | Biological properties of N-acyl and N-haloacetyl neuraminic acids: processing by enzymes of sialic acid metabolism, and interaction with influenza virus. |
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[19] |
---|
PubMed ID | 12711733 |
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Journal | Proc Natl Acad Sci U S A |
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Year | 2003 |
---|
Volume | 100 |
---|
Pages | 5694-9 |
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Authors | Joerger AC, Mayer S, Fersht AR |
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Title | Mimicking natural evolution in vitro: an N-acetylneuraminate lyase mutant with an increased dihydrodipicolinate synthase activity. |
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comments | This enzyme catalyzes the following reactions (according to the literature [13]): (A) Ring-opening through eliminative double-bond formation. (B) Schiff-base formation. (B1) Lys164 makes a nucleophilic attack on the C2 carbonyl carbon, forming carbinolamine cation. Here, a proton transfer from the nitrogen of Lys164 to the carbonyl oxygen occurs. (B2) Further transfer of a proton from the nitrogen to the hydroxyl oxgen of the carbinolamine cation gives the oxonium intermediate. (These proton transfers might be assisted by Tyr136 as acid-base.) (B3) The lone pair of the Lys amine attacks on the C2 carbon, leading to the dehydration of the oxonium, which results in the formation of Schiff-base intermediate (or immonium intermediate) and double-bond between the nitrogen and the C2 atom. (B4) Gly188 oxygen atom might stabilize the Schiff-base, indirectly by interacting with the O4 oxygen atom. (C) Eliminative double-bond formation. (C1) Substrate carboxylate acts as a general base to deprotonate the O4 hydroxylg group, through the sidechain of Tyr136. (C2) The deprotonation of the hydroxyl group leads to the bond cleavage between the C4 and C3 atoms, resulting in the formation of the O4 carbonyl oxygen and the enamine intermediate bound to Lys164. This step releases a product, N-acetylmannosamine. (D) Isomerization (change in the position of double-bond; tautomerization). (D1) Substrate carboxylate acts as a general acid to protonate the C3 methylene carbon atom, through the sidechain of Tyr136, leading to the formation of imine intermediate from the enamine. (E) Schiff-base deformation. (E1) Water makes a nucleophilic attack on the C2 carbon, forming the oxonium intermediate. (E2) A proton transfer from the oxonium group to the Lys164 nitrogen leads to the formation of carbinolamine cation. (E3) The lone pair of the hydroxyl oxygen attacks on the C2 carbon, leading to the elimination of Lys164, which results in the formation of another product, pyruvate. The ring-closure of N-acetylmannosamine occurs spontaneously (see [13]).
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created | updated |
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2004-05-26 | 2009-02-26 |
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