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CATH domain | Related DB codes (homologues) |
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2.40.70.10 : Cathepsin D, subunit A; domain 1 | D00471,D00436,D00438,D00439,D00440,D00441,D00442,D00443,D00437,D00423,D00445,D00484,M00206,M00166,D00231,D00529 |
UniProtKB:Accession Number | P46925 |
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Entry name | PLM2_PLAFA |
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Activity | Hydrolysis of the bonds linking certain hydrophobic residues in hemoglobin or globin. Also cleaves small molecules substrates such as Ala-Leu-Glu-Arg-Thr-Phe-|-Phe(NO(2))- Ser-Phe-Pro-Thr. |
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Subunit |
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Subcellular location | Vacuole. |
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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 | C00017 | C00012 | C00001 | C00017 | C00012 | I00136 |
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Compound | Protein | Peptide | H2O | Protein | Peptide | Amino-diol-tetrahedral intermediate |
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Type | peptide/protein | peptide/protein | H2O | peptide/protein | peptide/protein |
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ChEBI |
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| 15377
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PubChem |
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| 962 22247451
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| | | | | | | | | | | | | |
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1pfzA01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1pfzB01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1pfzC01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1pfzD01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1smeA01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA(chain C) |
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1smeB01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA(chain D) |
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1leeA01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Transition-state-analogue:R36 |
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1lf2A01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Transition-state-analogue:R37 |
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1lf3A01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Transition-state-analogue:EH5 |
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1lf4A01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1m43A01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA(chain C) |
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1m43B01 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA(chain D) |
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1pfzA02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1pfzB02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1pfzC02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1pfzD02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1smeA02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1smeB02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1leeA02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1lf2A02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1lf3A02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1lf4A02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1m43A02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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1m43B02 |  |  |  |  |  |  |  | Unbound | Unbound | | Unbound | Unbound | Unbound |
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References for Catalytic Mechanism | References | Sections | No. of steps in catalysis |
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[1] | Fig.5, p.7010-7011 | 3 | [3] | p.16170-16172 |
| [16] | Scheme 1, p.175-176 |
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references | [1] |
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PubMed ID | 3313384 |
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Journal | Proc Natl Acad Sci U S A |
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Year | 1987 |
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Volume | 84 |
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Pages | 7009-13 |
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Authors | Suguna K, Padlan EA, Smith CW, Carlson WD, Davies DR |
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Title | Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action. |
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[2] |
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Comments | X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS). |
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Medline ID | 96413592 |
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PubMed ID | 8816746 |
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Journal | Proc Natl Acad Sci U S A |
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Year | 1996 |
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Volume | 93 |
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Pages | 10034-9 |
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Authors | Silva AM, Lee AY, Gulnik SV, Maier P, Collins J, Bhat TN, Collins PJ, Cachau RE, Luker KE, Gluzman IY, Francis SE, Oksman A, Goldberg DE, Erickson JW |
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Title | Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum. |
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Related PDB | 1sme |
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Related UniProtKB | P46925 |
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[3] |
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PubMed ID | 9405050 |
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Journal | Biochemistry |
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Year | 1997 |
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Volume | 36 |
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Pages | 16166-72 |
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Authors | Xie D, Gulnik S, Collins L, Gustchina E, Suvorov L, Erickson JW |
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Title | Dissection of the pH dependence of inhibitor binding energetics for an aspartic protease: direct measurement of the protonation states of the catalytic aspartic acid residues. |
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[4] |
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PubMed ID | 9561243 |
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Journal | Adv Exp Med Biol |
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Year | 1998 |
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Volume | 436 |
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Pages | 363-73 |
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Authors | Silva AM, Lee AY, Erickson JW, Goldberg DE |
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Title | Structural analysis of plasmepsin II. A comparison with human aspartic proteases. |
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[5] |
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PubMed ID | 9873703 |
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Journal | Bioorg Med Chem Lett |
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Year | 1998 |
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Volume | 8 |
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Pages | 3203-6 |
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Authors | Carroll CD, Johnson TO, Tao S, Lauri G, Orlowski M, Gluzman IY, Goldberg DE, Dolle RE |
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Title | Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D. |
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[6] |
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PubMed ID | 9873534 |
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Journal | Bioorg Med Chem Lett |
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Year | 1998 |
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Volume | 8 |
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Pages | 2315-20 |
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Authors | Carroll CD, Patel H, Johnson TO, Guo T, Orlowski M, He ZM, Cavallaro CL, Guo J, Oksman A, Gluzman IY, Connelly J, Chelsky D, Goldberg DE, Dolle RE |
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Title | Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library. |
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[7] |
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PubMed ID | 10212129 |
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Journal | J Med Chem |
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Year | 1999 |
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Volume | 42 |
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Pages | 1428-40 |
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Authors | Haque TS, Skillman AG, Lee CE, Habashita H, Gluzman IY, Ewing TJ, Goldberg DE, Kuntz ID, Ellman JA |
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Title | Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II. |
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[8] |
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Comments | X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF ZYMOGEN. |
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Medline ID | 99101380 |
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PubMed ID | 9886289 |
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Journal | Nat Struct Biol |
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Year | 1999 |
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Volume | 6 |
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Pages | 32-7 |
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Authors | Bernstein NK, Cherney MM, Loetscher H, Ridley RG, James MN |
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Title | Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum. |
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Related PDB | 1pfz |
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Related UniProtKB | P46925 |
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[9] |
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PubMed ID | 10500110 |
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Journal | Proc Natl Acad Sci U S A |
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Year | 1999 |
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Volume | 96 |
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Pages | 10968-75 |
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Authors | Khan AR, Khazanovich-Bernstein N, Bergmann EM, James MN |
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Title | Structural aspects of activation pathways of aspartic protease zymogens and viral 3C protease precursors. |
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[10] |
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PubMed ID | 10548045 |
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Journal | Protein Sci |
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Year | 1999 |
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Volume | 8 |
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Pages | 2001-9 |
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Authors | Westling J, Cipullo P, Hung SH, Saft H, Dame JB, Dunn BM |
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Title | Active site specificity of plasmepsin II. |
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[11] |
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PubMed ID | 11502532 |
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Journal | Antimicrob Agents Chemother |
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Year | 2001 |
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Volume | 45 |
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Pages | 2577-84 |
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Authors | Jiang S, Prigge ST, Wei L, Gao Ye, Hudson TH, Gerena L, Dame JB, Kyle DE |
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Title | New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins. |
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Related PDB | 1j8j |
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[12] |
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PubMed ID | 12189138 |
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Journal | J Biol Chem |
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Year | 2002 |
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Volume | 277 |
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Pages | 41009-13 |
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Authors | Siripurkpong P, Yuvaniyama J, Wilairat P, Goldberg DE |
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Title | Active site contribution to specificity of the aspartic proteases plasmepsins I and II. |
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[13] |
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PubMed ID | 11975483 |
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Journal | J Nat Prod |
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Year | 2002 |
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Volume | 65 |
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Pages | 476-80 |
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Authors | Hu JF, Schetz JA, Kelly M, Peng JN, Ang KK, Flotow H, Leong CY, Ng SB, Buss AD, Wilkins SP, Hamann MT |
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Title | New antiinfective and human 5-HT2 receptor binding natural and semisynthetic compounds from the Jamaican sponge Smenospongia aurea. |
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[14] |
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PubMed ID | 12009321 |
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Journal | Phytochemistry |
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Year | 2002 |
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Volume | 60 |
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Pages | 175-7 |
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Authors | Ovenden SP, Cao S, Leong C, Flotow H, Gupta MP, Buss AD, Butler MS |
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Title | Spermine alkaloids from Albizia adinocephala with activity against Plasmodium falciparum plasmepsin II. |
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[15] |
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PubMed ID | 12454457 |
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Journal | Acta Crystallogr D Biol Crystallogr |
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Year | 2002 |
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Volume | 58 |
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Pages | 2001-8 |
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Authors | Asojo OA, Afonina E, Gulnik SV, Yu B, Erickson JW, Randad R, Medjahed D, Silva AM |
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Title | Structures of Ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 A in complex with the inhibitors rs367 and rs370. |
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Related PDB | 1lee,1lf2 |
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[16] |
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PubMed ID | 12614616 |
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Journal | J Mol Biol |
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Year | 2003 |
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Volume | 327 |
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Pages | 173-81 |
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Authors | Asojo OA, Gulnik SV, Afonina E, Yu B, Ellman JA, Haque TS, Silva AM |
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Title | Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum. |
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Related PDB | 1m43,1lf3,1lf4 |
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comments | This enzyme belongs to the peptidase family-A1. According to the literature [3] & [16], this enzyme has got a catalytic dyad, composed of two aspartate residues. One is ionized and the other is protonated around the physiological pH. The paper [1] proposed a catalytic mechanism for its homologous enzyme. Accoriding to the proposed mechanism, the sidechains of both the aspartic acid residues are hydrogen-bonded to the catalytic water. The sidechain of the ionized aspartate (possibly corresponding to Asp214) might act as a general base, which can abstract a proton from the water, which in turn would make a nucleophilic attack on the carbonyl carbon of the peptide bond. Meanwhile, the protonated sidechain of the other aspartate (corresponding to Asp34) may stabilize the negative charge on the carbonyl oxygen of the scissile bond during the transition state. At the next stage, the sidechain of the aspartate that had accepted a proton from water could protonate the leaving nitrogen atom, as a general acid, during the cleavage of the peptide bond.
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created | updated |
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2003-10-17 | 2012-06-28 |
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