Proteins and Enzymes 3

Proteins and Enzymes 3

Proteins and Enzymes 3

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Enzymes

  • Enzymes are catalysts for biochemical reactions. Virtually every chemical reaction in a biological system is regulated by an enzyme
  • A catalyst does not change the outcome of a reaction but effects the rate of a reacton. A catalyst unaltered by the reaction
  • Enzymes accelerate the rate of a biochemical reaction by lowering the activation energy for that reaction

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Enzymes

  • Enzymes achieve catalysis of a reaction by reducing the activation energy (the energy barrier to the reaction)
  • Physically this is achieved by the correct and precise orientation of the substrate within the enzyme active site
  • Enzyme reactions are:
    • Fast - most reactions are at least a million times faster in the presence of an enzyme
    • Specific - for the substrates. Enzymes can also distinguish between functional groups, isomers and enantiomers within a substrate
    • Efficient - enzymes have evolved to minimises waste by-products
  • Many drugs interact with enzymes and disrupt their function
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Enzymes

  • Enzymes are globular proteins (tertiary structure)
  • Tertiary structure creates active site pockets. Reactants fit tightly and interact with the protein (lowering the activation energy of the reaction)
  • Globular proteins can bind one or more substances in an active site: the substrate(s) and any cofactors that may be required for the reaction
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Enzyme Nomenclature

  • Enzymes are named and classified according to the reactions catalysed
  • Trivially, the suffix '-ase' is added to the name of the substrate or a descriptive term for the type of reaction
  • The International Union of Biochemistry categorises enzymes into six major groups according to the general class of chemical reactions they catalyse:
    • Oxidoreductases, transferases, hydrolases, lyases, isomerasesand ligases
  • The enzyme commission assigns a unique code number to each enzyme, e.g. 3.2.1.4
  • Which of the six main classes, the sub-class, the sub-sub-class, the serial number of the enzyme in the sub-sub-class
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Enzyme Cofactors

  • Enzymes are composed of 20 amino acids . There is limited chemistry possible with 20 different side chains. Cofactors supply chemical groups not otherwise found in active sites
  • Many enzymes are inactive as a protein alone (apoenzymes) and cofactors are required for activity
  • Cosubstrates: weakly bound to the enzyme. Altered during the course of the reaction and dissociate from the active site (regenerated in another enzymic reaction and recycled)
  • Prosthetic groups: tightly bound to the enzyme but must be regenerated each catalytic cycle

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Essential Ions

  • Nearly a third of proteins require a metal ion for activity. They are known as metalloproteins or metalloenzymes
  • Fe2+ found in haem (haemoglobin, myoglobin)
  • Mg2+ many kinases (reactions involving phosphorylations
  • Zn2+ many enzymes (oxidations/reuctions, DNA recognition)
  • Copper, manganese, cobalt, molybdenum are other trace metals used by enzymes
    • Cobalt deficiency leads to pernicious anemia (low red blood cell count, neurological deterioration)
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Enzyme Class 1: Oxidoreductases

  • Catalyse oxidation and reduction (REDOX) reactions. Enzymes in this class include dehydrogenases, oxidases, peroxidases, reductases
  • An example is alcohol dehydrogenase oxidises ethanol to ethanal (acetaldehyde), using a cofactor NAD+ and a metal ion, zinc
  • NAD+ is the biologically active form of vitamin B3 (niacin)
  • NAD+ is a cosubstrate for alcohol dehydrogenase
  • The enzyme orientates all species correctly for reaction to occur

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Enzyme Class 2: Transferases

  • Transferases catalyse functional group transfer reactions. Includes kinases, an important family of enzymes that catalyse phosphorylation reactions
  • Transcarboxylase catalyses the simultaneous conversion of propionyl coenzyme A to methyl malonyl coenzyme A and oxaloacetate to pyruvate - important metabolic reactions
  • Biotin is a cofactor frequently involved in enzymic carboxylation reactions because of its ability to bind and manipulate a carboxylate group

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Enzyme Class 3: Hydrolases

  • Catalyse hydrolysis reactions (the breaking of a bond by the addition of water across it). Trypsin mediates the hydrolysis of Lys-aa or Arg-aa peptide bonds
  • Trypsin is a serine protease enzyme. It needs no cofactor, its active site contains sufficient functionality to be able to perform the reaction unassisted

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Trypsin: Mechanism of Action

  • The serine residue attacks the substrate peptide carbonyl bond, aided by the Asp and His which promote the nucleophilic attack and stabilise the resulting positive charge
  • The tetrahedral intermediate collapses liberating R-NH2, but the carboxyl residue remains bonded to the enzyme, via the serine (an ester linkage - easily hydrolysed)
  • A water molecule, correctly orientated by interaction with the His, attacks the ester carbonyl group
  • Reaction complete. Active site amino acids are unchanged and ready for further catalysis. New amino and carboxylic groups exposed by hydrolysis
  • Trypsin uses the chemical groups of its active site amino acid side chains to perform a complex reaction, and needs no cofactor
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Enzyme Class 4: Lyases

  • Catalyse bond breaking reactions (but not hydrolytic or oxidative bond breaking)
  • e.g. L-dopa decarboxylase - decarboxylation of L-aimino acids

  • Coenzyme involved: pyridoxal phosphate  (vitamin B6)
  • Complex mechanism: the aldehyde group reacts with amines (drug) to form an imine (-CH=N). Aldehydes are not available in amino acid side chains, therefore a vitamin is required
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Enzyme Class 5: Isomerases

  • Catalyse isomerisation reactions, i.e. the rearrangement of groups within a substrate molecule, E.g. alanine racemase found in bacteria and catalyses the interconversion of L and D-alanine. D-alanine is essential for bacterial cell wall 
  • Coenzyme involved: Pyridoxal phosphate (vitamin B6)
  • Enzyme removes H from one face of amino acid (A) and replaces on opposite face (B)

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Enzyme Class 6: Ligases

  • Catalyse the ligation (joining) of two substrates. Pyruvate carboxylase joins pyruvate with carbon dioxide to generate oxaloacetate. Important in metabolism/Krebs cycle

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