Catalytic triad
A catalytic triad usually refers to the three amino acid residues found inside the active site of certain protease enzymes: serine (S), aspartate (D), and histidine (H). This trio works together to break peptide bonds on polypeptides. In general terms, catalytic triad can refer to any set of three residues that function together and are directly involved in catalysis. Because enzymes fold into complex three-dimensional shapes, the residues of a catalytic triad can be far from each other in the along the primary structure amino-acid sequence; however, they are brought close together when the chain folds into its 3-dimensional tertiary structure.
Example
An example of a catalytic triad is present in chymotrypsin, wherein the triad (on the enzyme) consists of S195 (that is, the serine found at residue 195 in the protein sequence), D102 and H57. In essence, S195 binds to the substrate polypeptide to the side of a phenylalanine, tryptophan, or tyrosine residue (the residue is on the C-terminus side), holding it in place. D102 and H57 then hydrolyze the bond. This takes place in several steps.
- Upon binding of the target protein, the carboxylic group (-COOH) on D102 forms a low-barrier hydrogen bond with H57, increasing the pKa of its imidazole nitrogen from 7 to about 12. This allows H57 to act as a powerful general base, and deprotonate S195.
- The deprotonated S195 serves as a nucleophile, attacking the carbonyl carbon on the C-terminal side of the residue and forcing the carbonyl oxygen to accept an electron, and transforming the sp2 carbon into a tetrahedral intermediate. This intermediate is stabilized by an oxanion hole, which also involves S195.
- Collapse of this intermediate back to a carbonyl causes H57 to donate its proton to the nitrogen attached to the alpha carbon. The nitrogen and the attached peptide fragment (c-terminal to the F W or Y residue) leave by diffusion.
- A water molecule then donates a proton to H57 and the remaining OH- attacks the carbonyl carbon, forming another tetrahedral intermediate. The OH is a poorer leaving group than the C-terminal fragment, so, when the tetrahedral intermediate collapses again, S195 leaves and regains a proton from H57.
- The cleaved peptide, now with a carboxyl end, leaves by diffusion.
Amino acid sequence, histidine 57
For three example proteases, chymotrypsin A (cow), trypsin (cow), and elastase (pig), the amino acid residues are listed in the following table; the (vertical column)-histidine 57, is coded as capital H:[1]
(see: Sequence of proteases - chymotrypsin A - trypsin - elastase)
A few sections are shown as very similar, and likewise sections that are quite dissimilar-(the sections away from the "active 3-dimensional site"). From the residues 46-99A, the most common area is from residue 46 to 58, one residue past residue Histidine 57; it is even more similar, from the residues 51-58.
| x | 46-50 | 51 - 55 | 56,57-60 | 65 | 65A 66-70 |
|---|---|---|---|---|---|
| C | LINEN | WVVTA | AHCGV | TTSDV | 'VVAGEFD |
| T | LINSQ | WVVSA | AHCYK | SGIQV | RL'`GQDN |
| E | LIRQN | WVMTA | AHCVD | RELTF | RVVVGEHN |
| x | 73-75-80 | 85 | 90 | 95 | 96-99A |
|---|---|---|---|---|---|
| C | QGSSSEKI | QKLKI | AKVFK | NSKYN | SLTI' |
| T | INVVEGNQ | QFISA | SKSIV | HPSYN | SNTL' |
| E | LNQNNGTE | QYVGV | QKIVV | HPYWN | TDDVA |
Four atom characterize different ASP-HIS-SER enzyme families
By scanning the whole Protein Data Bank, containing the 3D structures of proteins, for the presence of the catalytic triad, one can find several hundred protein structures with the triad,.[2][3] It is interesting that the relative positions of just four atoms (circled by red on the figure to the right) well characterize different triad-containing enzyme families
See also
References
- ^ Wilson, Eisner, Briggs, Dickerson, Metzenberg, O'Brien, Susman, & Boggs. Life on Earth, Chapter: Molecular Evolution, Graphic: Sequences of Four Proteases, (cow and pig, etc.) p. 816-817.
- ^ "Triad database". www.pitgroup.org. Retrieved 2012-06-15.
- ^ Ivan, Gabor; et al. (2009). "Four Spatial Points That Define Enzyme Families". Biochemical and Biophysical Research Communications. 383 (4). Elsevier: 417–420. doi:10.1016/j.bbrc.2009.04.022.
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- Lehninger, Principles of Biochemistry, 4th ed. (pp 216–219)
- Wilson, Eisner, Briggs, Dickerson, Metzenberg, O'Brien, Susman, & Boggs. Life on Earth, Edward O. Wilson, Thomas Eisner, Winslow R. Briggs, Richard E. Dickerson, Robert L. Metzenberg, Richard D. O'Brien, Millard Susman, William E. Boggs, c 1973, Sinauer Associates, Inc., Publisher, Stamford, Connecticut. 1033 pp, 19 p Index & Back Page (hardcover, ISBN 0-87893-934-2)