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Dr. Prabha Arya Assistant Professor Deshbandhu College Dr. Prabha Arya Assistant Professor Deshbandhu College 1 Enzymes Complex Enzymes (Protein Simple Enzymes and non- (Whole Protein) proteinaceous part) Apoenzymes Cofactor (Non- (Proteinaceous Protein part) part) Cofactor Inorganic Coenzymes metal (made of enzymes vitamins) Biochemistry, Voet D and Voet J G, 4th Edition A variety of interesting chemical rearrangements occur in the catabolic pathways of amino acids. PLP, THF, Biotin and S-adenosylmethionine PLP is involved in transamination reactions Rest are involved in one carbon transfer reaction from most reduced to most oxidized form (of carbon) Lehninger: Principles of Biochemistry, Nelson D L and Cox M M, 7th edition. THF is a 6-methylpterin derivative linked in sequence to p-aminobenzoic acid and Glu residues. Up to five additional Glu residues may be linked to the first glutamate via isopeptide bonds to form a polyglutamyl tail. THF is more versatile than other cofactors in that it functions to transfer C1 units in several oxidation states. The oxidized form, folate, is a vitamin for mammals; it is converted in two steps to tetrahydrofolate by the enzyme dihydrofolate reductase. Biochemistry, Voet D and Voet J G, 4th Edition The two-stage reduction of folate to THF. Both reactions are catalyzed by dihydrofolate reductase (DHFR). The one-carbon group undergoing transfer, in any of three oxidation states, is bonded to N-5 or N-10 or both. The most reduced form of the cofactor carries a methyl group, a more oxidized form carries a methylene group, and the most oxidized forms carry a methenyl, formyl, or formimino group. Most forms of tetrahydrofolate are interconvertible and serve as donors of one-carbon units in a variety of metabolic reactions. The primary source of one-carbon units for tetrahydrofolate is the carbon removed in the conversion of serine to glycine, producing N5,N10 methylenetetrahydrofolate. THF as coenzyme for carbon transferring reaction in various forms Lehninger: Principles of Biochemistry, Nelson D L and Cox M M, 7th edition. One form of methionine synthase common in bacteria uses N5-methyltetrahydrofolate as a methyl donor. Another form of the enzyme present in some bacteria and mammals uses N5-methyltetrahydrofolate, but the methyl group is first transferred to cobalamin, derived from coenzyme B12, to form methylcobalamin as the methyl donor in methionine formation. This reaction and the rearrangement of L- methylmalonyl-CoA to succinyl-CoA are the only known coenzyme B12–dependent reactions in mammals. Vitamin B7 or Biotin (also known as Vitamin H) Pyruvate Carboxylase Has a Biotin Prosthetic Group Biotin consists of an imidazoline ring that is cis-fused to a tetrahydrothiophene ring bearing a valerate side chain.The chirality at each of its three asymmetric centers is indicated. Positions 1, 2, and 3 constitute a ureido group. Lehninger: Principles of Biochemistry, Nelson D L and Cox M M, 7th edition. In carboxybiotinyl– enzyme, N1 of the biotin ureido group is the carboxylation site. Biotin is covalently attached to carboxylases by an amide linkage between its valeryl carboxyl group and the ε- amino group of an enzyme Lys side chain to form biocytin. Lehninger: Principles of Biochemistry, Nelson D L and Cox M M, 7th edition. The biotin ring system is therefore at the end of a 16-Å-long flexible arm. Phase I Biotin is carboxylated at its N1 atom by Phase II bicarbonate ion in a three-step reaction in which the hydrolysis of ATP to ADP The activated + Pi functions, via the intermediate formation of carboxyphosphate, to carboxyl group is dehydrate bicarbonate. transferred from This yields free CO2, which has sufficient free energy to carboxylate carboxybiotin to biotin. pyruvate in a The resulting carboxyl group is activated relative to bicarbonate (G°`for three-step its cleavage is 19.7 kJ mol-1) and can therefore be transferred without further reaction to form free energy input. oxaloacetate. These two reaction phases occur on different active sites of the same enzyme. Lehninger: Principles of Biochemistry, Nelson D L and Cox M M, 7th edition. Phase I is a three-step reaction in which carboxyphosphate is formed from bicarbonate and ATP, followed by the generation of CO2 on the enzyme, which then carboxylates biotin. Phase II is a three-step reaction in which CO2 is produced at the active site via the elimination of the biotinyl enzyme, which accepts a proton from pyruvate to generate pyruvate enolate. This, in turn, nucleophilically attacks the CO2, yielding oxaloacetate. Lehninger: Principles of Biochemistry, Nelson D L and Cox M M, 7th edition. Pyridoxine (Vitamin B6) Forms the Coenzyme Pyridoxal Phosphate Pyridoxine, pyridoxamine, and pyridoxal, are naturally occurring forms of vitamin B6. They are efficiently converted to pyridoxal phosphate. Pyridoxal phosphate is essential for the transaminase reactions that allow the inter conversion of amino acids and their entry into energy generating pathways and can, therefore, be considered an energy-releasing vitamin . Text book of Biochemistry with clinical correlation, Devlin T M, 7th edition • Pyridoxal phosphate is generally covalently bound to the enzyme’s active site through an aldimine (Schiff base) linkage to the ε-amino group of a Lys residue Pyridoxal phosphate participates in a variety of reactions at the α , β and γ carbons (C-2 to C-4) of amino acids. • Reactions at the carbon include racemizations (interconverting L- and D-amino acids) and decarboxylations, as well as transaminations. Pyridoxal phosphate plays the same chemical role in each of these reactions. • A bond to the carbon of the substrate is broken, removing either a proton or a carboxyl group. The electron pair left behind on the carbon would form a highly unstable carbanion, but pyridoxal phosphate provides resonance stabilization of this intermediate. Lehninger: Principles of Biochemistry, Nelson D L and Cox M M, 7th edition. The highly conjugated structure of PLP (an electron sink) permits delocalization of the negative charge. Aminotransferases are classic examples of enzymes catalyzing bimolecular Ping- Pong reactions, in which the first substrate reacts and the product must leave the active site before the second substrate can bind. Thus the incoming amino acid binds to the active site, donates its amino group to pyridoxal phosphate, and departs in the form of an α-keto acid. The incoming α-keto acid then binds, accepts the amino group from pyridoxamine phosphate, and departs in the form of an amino acid. a. Aminotransferase Reactions Occur in Two Stages 1. The amino group of an amino acid is transferred to the enzyme, producing the corresponding keto acid and the aminated enzyme. 2. The amino group is transferred to the keto acid acceptor (e.g., α-ketoglutarate), forming the amino acid product (e.g., glutamate) and regenerating the enzyme. Biochemistry, Voet D and Voet J G, 4th Edition The first stage of the reaction, in which the -amino group of an amino acid is transferred to PLP yielding an -keto acid and PMP, consists of three steps: (1) transimination; Step 1. The amino acid’s nucleophilic amino group attacks the enzyme–PLP Schiff base carbon atom in a transimination (trans-Schiffization) reaction to form an amino acid–PLP Schiff base (aldimine), with concomitant release of the enzyme’s Lys amino group. This Lys is then free to act as a general base at the active site. Biochemistry, Voet D and Voet J G, 4th Edition Step 2. The amino acid–PLP Schiff base tautomerizes to an α-keto acid–PMP Schiff base by the active site Lys–catalyzed removal of the amino acid hydrogen and protonation of PLP atom C4. via a resonance-stabilized carbanion intermediate.This resonance stabilization facilitates the cleavage of the C-H bond. Lys released during the transimination reaction acts as a general acid–base catalyst; Biochemistry, Voet D and Voet J G, 4th Edition Step 3. The -keto acid–PMP Schiff base is hydrolyzed to PMP and an α-keto acid. The second stage of the reaction, in which the amino group of PMP is transferred to a different α-keto acid to yield a new α-amino acid and PLP, is essentially the reverse of the first stage: Steps 3., 2., and 1. are, respectively, the reverse of Steps 3, 2, and 1. To complete the aminotransferase’s catalytic cycle, the coenzyme must be converted from PMP back to the enzyme–PLP Schiff base. This involves the same three steps as earlier, but in reverse order: Step 3. PMP reacts with an -keto acid to form a Schiff base. Step 2. The α-keto acid–PMP Schiff base tautomerizes to form an amino acid–PLP Schiff base. Step 1. The ε-amino group of the active site Lys residue attacks the amino acid–PLP Schiff base in a transimination reaction to regenerate the active enzyme–PLP Schiff base, with release of the newly formed amino acid. Thiamine Pyrophosphte: The thiazolium ring constitutes its catalytically active functional group. Biochemistry, Voet D and Voet J G, 4th Edition TPP is formed from vitamin B1 Thiamine Text book of Biochemistry with clinical correlation, Devlin T M, 7th edition Thiamine pyrophosphate plays role in the cleavage of bonds adjacent to a carbonyl group, such as the decarboxylation of α-keto acids, and in chemical rearrangements in which an activated acetaldehyde group is transferred from one carbon atom to another. The functional part of TPP, the thiazolium ring, has a relatively acidic proton at C-2. Loss of this proton produces a carbanion that is the active species in TPP-dependent reactions. The carbanion readily adds to carbonyl groups, and the thiazolium ring is thereby positioned to act as an ―electron sink‖ that greatly facilitates reactions such as the decarboxylation catalyzed by pyruvate decarboxylase. Biochemistry, Voet D and Voet J G, 4th Edition (a) The reactive carbon atom in the thiazolium ring (red).
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