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How enzymes catalyze reactions? Organic chemistry of vitamins

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1 How enzymes catalyze reactions? Organic chemistry of vitamins

2 Book: Bruice Chapter: 17 Pages:

3 Enzyme-catalyzed reactions
Reactant of an enzyme catalysis – substrate Substrate + Enzyme -> Product Substrate binds in a pocket of enzyme – active site All bond-breaking and bon-forming steps occur in that moment Enzymes – specific for the substrates Specificity of enzymes – molecular recognition

4 Specificity – results from its conformation and the particular amino acid side chains (α-substituents) that are at the active site Example: AA with negatively charged side chain associates with a positively charged group on the substrate

5 Factors Influence catalytic ability of enzymes:
• Reacting groups are brought together at the active site in the proper orientation for reaction. • Some of the amino acid side chains of the enzyme serve as catalysts. These are positioned relative to the substrate precisely where they are needed for catalysis. • Amino acid side chains can stabilize transition states and intermediates—by van der Waals interactions, electrostatic interactions, and hydrogen bonding—which makes them easier to form.

6 Enzyme mechanism “ase” – tells something about the reaction it catalyzes Example: glucose-6-phosphate isomerase catalyzes an isomerization reaction that converts glucose-6-phosphate to fructose-6-phosphate open-chain form of glucose is an aldohexose open-chain form of fructose is a ketohexose glucose-6-phosphate isomerase—converts an aldose to a ketose

7 Enzyme must open the six-membered-ring sugar
convert it to the five-membered-ring sugar This enzyme – has at least 3 catalytic groups at its active site One functioning as an acid catalyst and two acting as base catalyst

8 1. ring opening reaction: (base catalyst-His) removes a proton and acid catalyst aids the departure of leaving group by protonation 2. base catalyst (Glu residue) removes a proton from α-carbon of aldehyde 3. enol converted to a ketone 4. conjugate acid and conjugate base from corresponding acid and base close the ring

9 The mechanism of aldolase
Involved in glycolysis D-glucose is substrate Final product – 2 molecules of pyruvate six-carbon compound must be cleaved into two three-carbon compounds Aldolase - catalyzes this cleavage The enzyme is called aldolase because the reverse reaction is an aldol addition

10 1. fructose-1,6-diphosphate forms an imine with a Lys residue at the active site of the enzyme
2. A Tyr residue functions as a base catalyst in the step that cleaves the bond between C-3 and C-4 3. The enamine intermediate rearranges to an imine, with the tyrosine residue now functioning as an acid catalyst 4. Hydrolysis of the imine releases dihydroxyacetone phosphate, the other three carbon product

11 Coenzymes and vitamins
Coenzymes – enzyme helpers organic molecules assist enzymes in catalyzing certain reactions that cannot be catalyzed by the amino acid side chains of the enzyme alone derived from organic compounds commonly known as vitamins Vitamin - substance needed in small amounts for normal body function that the body cannot synthesize The body synthesizes the coenzyme from the vitamin

12 2 classes: water and fat soluble
Fat soluble: A, D, E and K Vitamin K - only water-insoluble vitamin currently known to be a precursor for a coenzyme Vitamin A - for proper vision Vitamin D - regulates calcium and phosphate metabolism Vitamin E – antioxidant Water soluble: B complex (precursors for coenzymes) and vitamin C (no precursor) vitamin C is a radical inhibitor - must be included in their diets

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14 Niacin For redox reactions
Needs coenzyme – AA cannot perform redox reactions coenzyme serves as the oxidizing or reducing agent enzyme’s role is to hold the substrate and coenzyme together so that the oxidation or reduction reaction can take place most commonly used: nicotinamide adenine dinucleotide (NAD+)

15 composed of two nucleotides
linked together through their phosphate groups Nucleotide - heterocyclic compound attached to C-1 of a phosphorylated ribose Heterocyclic compound – one or more of the ring atoms is an atom other than carbon The heterocyclic component of one of the nucleotides of NAD+ is nicotinamide, and the heterocyclic component of the other is adenine The positive charge in the NAD+ abbreviation indicates the positively charged nitrogen of the substituted pyridine ring

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17 The adenine nucleotide for the coenzyme is provided by ATP
Niacin (vitamin B3) is the portion of the coenzyme that the body cannot synthesize and must acquire through the diet

18 Example: malate dehydrogenase
catalyzes an oxidation reaction of the secondary alcohol group of malate to a ketone group Oxidizing agent: NAD+ Number of C-H bonds decreases in an oxidation reaction

19 substrate is being oxidized, it donates a hydride ion (H-) to the 4-position of the pyridine ring of NAD+ The pyridine ring, therefore, is reduced The rest of the NAD+ molecule has the job of binding the coenzyme to the proper site on the enzyme basic amino acid side chain of the enzyme can help the oxidation reaction removing a proton from the oxygen atom of the substrate

20 The mechanism for reduction by NADH is the reverse of the mechanism for oxidation
When a substrate is being reduced, the dihydropyridine ring of NADH donates a hydride ion from its 4-position to the substrate ring, therefore, is oxidized An acidic amino acid side chain of the enzyme aids the reduction reaction by donating a proton to the substrate

21 Niacin deficiency Causes pellagra
Disease that begins with dermatitis and ultimately causes insanity and death Reported in 1927 in USA (120,000 cases) among poor people with unvaried diets

22 Vitamin B2 Flavin adenine dinucleotide (FAD) is another coenzyme used to oxidize substrates Example: FAD is the coenzyme used by succinate dehydrogenase to oxidize succinate to fumarate dinucleotide in which one of the heterocyclic compounds is flavin and the other is adenine instead of ribose, the flavin nucleotide has a reduced ribose (a ribitol group) – riboflavin or B2 Deficiency - inflammation of the skin

23 When FAD oxidizes a compound (S), FAD is reduced to FADH2

24 NAD+ or FAD? NAD+ - in enzyme-catalyzed oxidation reactions involving carbonyl compounds alcohols being oxidized to ketones, aldehydes, or carboxylic acids FAD - coenzyme used in other types of oxidations

25 Vitamin B1 Thiamine Absence in the diet - disease called beriberi
damages the heart, impairs nerve reflexes, and in extreme cases causes paralysis As vitamin - used to form the coenzyme thiamine pyrophosphate (TPP) required by enzymes that catalyze the transfer of a two-carbon fragment from one species to another

26 Example: Pyruvate decarboxylase requires TPP
catalyzes the decarboxylation of pyruvate and transfers the remaining two-carbon fragment to a proton, resulting in the formation of acetaldehyde

27 pyruvate dehydrogenase system - group of three enzymes and five coenzymes
overall reaction catalyzes the decarboxylation of pyruvate and transfers the remaining two-carbon fragment to coenzyme A - resulting in the formation of acetyl-CoA

28 Coenzyme A activates carboxylic acids by converting them to thioesters
more reactive than are carboxylic acids pKa of the conjugate acid of the thiol leaving group of a thioester is approx.10 The vitamin needed to make CoASH is pantothenate

29 Vitamin H Biotin unusual vitamin because it can be synthesized by bacteria that live in the intestine does not have to be included in our diet and deficiencies are rare can be found in people who maintain a diet high in raw eggs Egg whites contain a protein that binds biotin tightly and thereby prevents it from acting as a coenzyme When eggs are cooked, the protein is denatured, and the denatured protein does not bind biotin

30 required by enzymes that catalyze carboxylation of an α-carbon (a carbon adjacent to a carbonyl group) Carboxylases Example: acetyl-CoA carboxylase converts acetyl-CoA into malonyl-CoA Biotin-requiring enzymes use bicarbonate and also require ATP and Mg2+

31 Vitamin B6 pyridoxine or vitamin B6
coenzyme - pyridoxal phosphate (PLP) “al” suffix indicates that the coenzyme is an aldehyde deficiency -causes anemia; severe deficiencies can cause seizures and death PLP - required by enzymes that catalyze certain reactions of amino acids like decarboxylation

32 Vitamin B12 coenzyme B12 Has CN or HO- group coordinated with Cobalt
Humans must obtain all their vitamin B12 from their diet, particularly from meat deficiency - pernicious anemia Most deficiencies are caused by the intestines’ inability to absorb the vitamin

33 Enzymes that catalyze certain rearrangement reactions

34 Folic acid Tetrahydrofolate (THF) – coenzyme
used by enzymes that catalyze reactions that transfer a group containing a single carbon to their substrates produced by the reduction of two double bonds of folic acid (folate)

35 required for the synthesis of the bases found in DNA and RNA and for the synthesis of aromatic amino acids Three THF-coenzymes Methyl group transfer, methylene group transfer and formyl group transfer

36 Chemistry link: First antibiotics
Sulfonamides—commonly known as sulfa drugs 1936 as the first effective antibiotics sulfanilamide, the first sulfonamide, is structurally similar to p-aminobenzoic acid Sulfanilamide acts by inhibiting the enzyme that incorporates paminobenzoic acid into folate Both structures compete for the active site of the enzyme

37 Vitamin K for proper clotting of blood
K – koagulation (German word for clotting) Process requires Ca2+ Vitamin K needed for proper Ca2+ binding found in the leaves of green plants Deficiencies in the vitamin are rare because it is synthesized by intestinal bacteria Vitamin KH2 is the coenzyme form of the vitamin

38 Vitamin KH2 - coenzyme for the enzyme that catalyzes the carboxylation of the γ-carbon of glutamate side chains in proteins, forming γ-carboxyglutamates

39 Warfarin (coumadin) and dicoumerol - used as anticoagulants
Prevent clotting by inhibiting the enzyme that synthesizes vitamin KH2 from vitamin K epoxide enzyme cannot tell the difference between vitamin K epoxide and warfarin (or dicoumerol) - two compounds compete for binding at the enzyme’s active site Warfarin – common rat poison

40 Problems to solve Page 524

41 Summary Enzymes Substrate Active site Coenzyme Vitamins NAD+ and NADH
FAD and FADH2 TPP Biotin PLP Coenzyme B12 THF Vitamin KH2


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