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Lecture 10

Lecture 10 Cofactors coenzymes.docx

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Department
Biochemistry
Course
BCH210H1
Professor
Brunt
Semester
Fall

Description
Cofactors/Coenzymes  Cofactors required to convert inactive enzymes (apoenzymes) to active (holoenzymes)  Cofactors include: 1. Essential ions (metal) 2. Organic compounds – coenzymes  Activator ions – reversibly bound and often participate in binding substrates  Metal ions of metalloenzymes – some cations are tightly bound and participate directly in catalytic reactions  Cosubstrates – specific for chemical groups that accept and donate: o Hydrogen or electron  Prosthetic groups – large groups covalently attached at reactive centre o Can be derived from vitamins Essential ion cofactors  > 25% known enzymes require metallic cations for full catalytic function 1. Metal-activated enzymes – have an absolute requirement for added metal ions or alternatively are stimulated by addition of metal io+s 2+ 2+  Monovalent cations/divalent cations (e.g. K , Ca , Mg )  E.g. kinases require Mg 2+for the magnesium-ATP complex used for the 2+ phosphoryl-group-donating substrate – Mg shields negatively charged phosphate groups of ATP making them more susceptible for Nu attack - 2. Metalloenzymes – contain tightly bound metal ions at their AS  Usually transition metals: iron and zinc, and sometimes copper and cobalt  Can function as E catalysts -  By attracting e , can polarize bonds  E.g. cofactor for carbonic anhydrase (Reaction of water and carbon dioxide – end product of aerobic respiration) is an electrophilic Zn2+ atom bound to the side chains of 3 histidine (imidazole rings) residues and a molecule of water  Optimal at pH 9 Rate of reaction for CA at different pHs Mechanism of CA 1. Zinc promotes ionization of water (deprotonation of water) 2. Binding of water to zinc ion favors formation of the TS by enhancing proton release and positioning water in close proximity to the carbon dioxide – 3. Results in nucleophilic OH attack on the carbon atom of carbondioxide (S) 4. Producing bicarbonate (P) that releases the enzyme 2+  E.g. RE made by bacteria that cleave foreign DNA are enzymes that require Mg for catalytic activity 2+  Many enzymes that act on phosphate-containing substrates require Mg  Ions of other metalloenzymes can undergo reversible redox by transferring electrons from a reduced substrate to an oxidized substrate o E.g. iron is art of the heme group of catalase which degrades H O 2 2  Nonheme iron is often found in metalloenzymes as iron-sulfur clusters o In each type of cluster, the iron atoms are complexed with equal number of sulfide ions (S ) and thiolate groups of cysteine residue side chains o Each cluster, whether it has 2 or 4 iron atoms can accept only one electron in an oxidation reaction Coenzymes – two types based on how they interact with apoenzyme (protein part minus coenzyme)  Both are part of the AS and provide reactive groups not available on the side chains of the reactive amino acid residues of the AS  Usually synthesized from simple precursors in prokaryotes, protists, fungi, and plants  Animals have lost the ability to synthesize coenzymes and must be provide with them or at a minimum their immediate precursors to survive (essential nutrients: vitamins) 1. Cosubstrates – altered during course of reaction and dissociates from AS o Cosubstrate regenerated by another enzyme o Continually recycled within a cell unlike an ordinary substrate o Usually shuttle mobile metabolic groups between different enzyme catalyzed reactions o Examples:  ATP – transfer of AMP creates pyrophosphate, donation of phosphoryl group, pyrophosphoryl, adenyl AMP, or adenosyl group  ADP, GTP, ubiquinone + +  NAD , NADP - nicotinamide coenzymes  Play a role in redox reactions – assist in transfer of electrons to and from metabolites + +  Oxidized forms NAD /NADP are electron deficient and reduced forms NADH/NADPH carry an extra electron pair in the form of a covalently bound hydride ion (to C-4) + +  NAD /NADP act as cosubstrates for dehydrogenases – they are bound in an extended conformation through βα repeats called Rossman folds  E.g. Lactate dehydrogenase:oxidoreductase catalyzes the reversible oxidation of lactate Mechanism of lactate dehydrogenase – His-195 is a base catalyst in the AS of the enzyme  His-195 removes a proton from C-2 OH group of lactate, resulting in the transfer of the - + hydride ion H from C-2 of the substrate to C-4 of the NAD  Arg-171 forms an ion pair with the carboxylate group of the substrate  S-adenosylmethionine: synthesized via reaction of methionine + ATP → S- adenosylmethione +Pi +PP i  Reacts with nucleophilic acceptors – it is donor of most methyl groups used in biosynthetic reactions  Required for conversion of hormone NE to epinephrine  Needed for methylation of phospholipids, proteins, DNA, RNA  In plants it is the precursor of the hormone ethylene which regulates fruit ripening  uridine diphosphate: glucose (UDP-glucose): involved in carbohydrate metabolism  Oxygen on phosphate of G1P attacks the α-phosphorus of UTP  PP is released and rapidly hydrolyzed  Mobile glycosyl group of UDP glucose which can be donated to a suitable acceptor releasing UDP  UDP glucose is regenerated when ATP donates a phosphoryl group to form UTP that can then react with G1P  Coenzyme A  Oxidat
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