Biochemistry Online: An Approach Based on Chemical Logic

Biochemistry Online

 CHAPTER 7 - CATALYSIS

B:  MECHANISMS OF ENZYME CATALYSIS

BIOCHEMISTRY - DR. JAKUBOWSKI

 004/12/16

Learning Goals/Objectives for Chapter 7B:  After class and this reading, students will be able to

  • identify the types of catalysis used in enzyme-catalyzed reactions given a detailed mechanism;
  • interpret kinetic experiments experiments varying substrate, inhibitors, pH, ion strength, and amino acid side chains (through chemical modification or site-specific mutagenesis) to better understand the catalytic mechanisms utilized in enzyme-catalyzed reactions;
  • identify potential rate limiting steps in enzyme catalyzed reaction mechanisms and simplify kinetic equations based on them;
  • generally describe the diversity, the critical active site residues and the biological activities of proteases;
  • describe the structure/function of the proteasome.

B8.  Links and References

The Enzyme Function Initiative is developing such tools to predict in vitro enzymatic and in vivo physiological functions of unknown enzymes.  

Uniprot, a web base resources that hold  protein sequence and functional information, has over 44 million protein sequences (derived from nucleotide sequences) and most have no well defined protein function.

Metabolic Docker:  uses molecular docking as a basis for predicting the function of enzymes. It supports docking both ground state and high energy intermediate forms of metabolites and commercially available compounds to protein structures

Other Types of Enzymes

The three enzymes studied above are all hydrolases - enzymes that catalyze the hydrolysis of bonds (either amide or acetal).  This is only one class of six different reaction types that have been categorized by the Enzyme Commission of the International Union of Biochemistry and Molecular Biology.  The six types (all external links) include:

EC1:  Oxidioreductases - oxdiation/reduction reactions (we will discuss these in Chapter 8B)

EC2:  Transferases - acyl, glycosyl, 1C, N, O, aldehydes, ketones, etc 

EC3:  Hydrolases

EC4:  Lyases - cleavage of C-C, C-O, C-N, C-S, etc. bonds

EC5:  Isomerases - racemases, epimerases, cis-trans isomerases

EC6:  Ligases - form C-C, C-O, C-N, etc bonds

Other Links

Enzyme Nomenclature Database:  Interactive site to search information on enzymes using EC system of nomenclature.

BRENDA:  (Brauschweig Enzyme Database) Comprehensive Enzyme Information System

KEGG PATHWAY:   collection of manually drawn pathway maps representing our knowledge on the molecular interaction and reaction networks using KEGG, Kyoto Encyclopedia of Genes and Genomes

FMM (From Metabolite to Metabolite) - reconstructs metabolic pathways from one metabolite to another

References

  1.  Fuguo Jiang and Jennifer A. Doudna. CRISPR–Cas9 Structures and Mechanisms. Annu. Rev. Biophys. 2017. 46:505–29
  2. Giulia Palermo et al. Striking Plasticity of CRISPR-Cas9 and Key Role of Non-target DNA, as Revealed by Molecular Simulations.  ACS Cent. Sci. 2016, 2, 756−763
  3. Ryan Cross, CRISPR’s breakthrough problem.  Chem. Eng. News. pg 28. February 13, 2017
  4. John van der Oost, New Tool for Genome Surgery.  Science, 339, pg 768 (2013)
  5. Wolan, D. et al. Small-Molecule Activators of a Proenzyme. Science 326, 853 (2009)
  6. Wang, Y. et al. Crystal structure of a rhomboid family intramembrane protease.  Nature.  444, 179 (2006)
  7. Freeman, M. Proteolysis within the membrane: rhomboids revealed.  Nature Reviews: Molecular Cell Biology. 5, p 188 (2004)
  8. Borman, S. Much ado about enzyme mechanisms.  C&EN.  pg 35 (Feb 23, 2004)
  9. Garcia-Cioloca, M. Goa, J., Karplus, M. and Truhlar, D. How Enzymes Work:  Analysis by modern rate theory and computer simulation  Science. 303, pg 186 (2004)
  10. Benkovic, St. & Hammes-Schiffer, S. A Perspective on Enzyme Catalysis.  Science. 301, pg 1196 (2003)
  11. Takasugi, N. et al. The role of presenilin cofactors in the γ-secretase complex.  Nature. 422, pg 438 (2003)
  12. Weihofen et al. Identification of Signal Peptide Peptidase, a Presenilin-Type Aspartic Protease. Science,  296, pp. 2156, 2215,
  13. Vocadlo. D. et al.  Catalysis by hen egg-white lysozyme proceeds via a covalent intermediate.  Nature. 412. pg 835 (2001)
  14. Walsh, C. Enabling the Chemistry of Life.  Great review article on enzymes mechanisms.   Nature. 409, pg 226 (2001)
  15. Koeller and Wong.  Enzymes for Chemical Synthesis.  Nature 409. pg 232 (2001)
  16. Simeonov et al. Blue-Fluorescent Antibodies. Science. 290, pg 286, 307 (2000)
  17. Huntington et al. Structure of a serpin-protease complex shows inhibition by deformation.  Nature. 407, pg 923 (2000)
  18. New Way to Study Closely related proteins (remodeling proteins to make them more susceptible to inhibition)  Science 289. pg 2029 (2000)
  19. Vocadlo et al. Catalysis by hen egg-white lysozyme proceeds via a covalent intermediate.  Nature. 412. pg 835 (2001)
  20. Istan and Deisenhofer. Structural Mechanism for Statin Inhibition of HMG-CoA Reductase. Science. 292, pg 1160 (2001)
  21. Heine et al. Observations of Covalent Intermediates in an Enzyme Mechanism at Atomic Resolution.  Science 294. pg 369 (2001)
  22. Carpenter et al. Structure of dehydorquinate synthase reveals an active site capable of multi-step catalysis.  Nature. 394, pg 299 (1998)
  23. Kohen et al. Tunnel Vision (on why activity of therophilic enzymes (>60oC)  is low or absent at mesophilic temperatures (< 40oC) - from reduction of flexibility of thermophilic enzymes at mesophilic temperatures  - quantum tunneling explanation).  Nature. 399, pg 417, 496 (1999)
  24. Finnin et al. Structure of a histone deacetylase homologue bound to the TSA and SAHA inhibitors (and mechanism).  Nature. pg 189, September 1999.
  25. Ondrechen. THEMATICS: A simple computational predictor of enzyme function from structure.  Proc. Natl. Acad. Sci. USA, 98, pg 12473 (2001 )

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