Organic chemistry of metabolic pathways

Book: Bruice Chapter: 20

2 types: catabolism and anabolism Metabolism - reactions that living organisms carry out to obtain the energy they need and to synthesize the compounds they require 2 types: catabolism and anabolism Catabolism: complex molecules -> simple molecules +energy Anabolism: simple molecules+energy -> complex molecules

every reaction that occurs in a living system is catalyzed by an enzyme holds the reactants and any necessary coenzymes in place orienting the reacting functional groups Catalyzing amino acid side chains in such a way that the enzyme-catalyzed reaction can take place

Digestion reactants required for all life processes ultimately come from our diet Catabolism – 4 stages 1. digestion – hydrolysis (mouth, stomach, small interstine)

2. conversion of products from the first stage Converted compunds enter the citric acid cycle compound must be either one of the compounds in the cycle itself - acetyl-CoA or pyruvate

3. citric acid cycle acetyl group of each molecule of acetyl-CoA is converted to two molecules of CO2 Metabolic energy is measured in terms of ATP Small amount formed in first 3 stages

4. every molecule of NADH formed in one of the earlier stages of catabolism is converted into three molecules of ATP in a process called oxidative phosphorylation most of the energy (ATP) provided by fats, carbohydrates, and proteins is obtained in the fourth stage of catabolism

ATP - PHOSPHORYL TRANSFER REACTIONS Without ATP, many important biological reactions could not occur Example: reaction of glucose with hydrogen phosphate to form glucose-6-phosphate does not occur because the 6-OH group of glucose would have to displace a very basic OH-group from hydrogen phosphate

ATP present - 6-OH group of glucose attacks the terminal phosphate of ATP, breaking a phosphoanhydride bond weaker bond than the pi-bond SN2 reaction ADP is a very good leaving group transfer of a phosphoryl group from ATP to glucose is an example of a phosphoryl transfer reaction

Conclusion: importance of ATP provides a reaction pathway involving a good leaving group for a reaction that cannot occur (or would occur very slowly) because of a poor leaving group.

The catabolism of fats Fats – 3 ester groups 1. step – hydrolyzed by enzymes to glycerol and three fatty acid molecules

Glycerol reacts with ATP to form glycerol-3-phosphate Enzyme for catalysis – kinase puts a phosphoryl group on its substrate

Secondary alcohol group - oxidized to a ketone NAD+ oxidizing agent Enzyme for catalysis – dehydrogenase Oxidizes its substrate Product: one of the compounds in the glycolytic pathway

Activation of fatty acids In order to be metabolized activated by being converted into a thioester

The fatty acid reacts with ATP, in a phosphoryl transfer reaction - the product is an acyl phosphate The acyl phosphate reacts with CoASH in a nucleophilic acyl substitution reaction

acyl-CoA is converted to acetyl-CoA In repeating process – β-oxidation Series of 4 reactions Each removes two carbons from the fatty acyl-CoA by converting them into acetyl-CoA Different enzymes

The catabolism of carbohydrates In the first stage of catabolism - acetal groups that hold glucose subunits together are hydrolyzed Formation of individual glucose molecules

Glucose is further on converted to pyruvate Glycolysis or glycolytic pathway (biochemistry)

The fates of pyruvate NAD+ used as oxidizing agent in glycolysis NADH produced – needs to be oxidized back to NAD+ If oxygen is present it serves as oxidizing agent If it is not present (in muscle cells when intense muscle activity causes all the oxygen to be depleted) – pyruvate serves as oxidizing agent Reduced to lactic acid

In aerobic conditions when oxygen is used - pyruvate is converted to acetyl-CoA Enters the citric acid cycle catalyzed by the pyruvate dehydrogenase system requires three enzymes and five coenzymes

In anaerobic conditions pyruvate is reduced to lactate In yeast - decarboxylated to acetaldehyde by pyruvate decarboxylase acetaldehyde is the compound that oxidizes NADH back to NAD+ Reduced to ethanol – for the production of alcohol beverages

Solve the problems

The catabolism of proteins First stage – proteins hydrolyzed to amino acids Second stage - amino acids are converted to acetyl-CoA or pyruvate or citric acid cycle intermediates Products of second stage - enter the citric acid cycle Further metabolized

Example: catabolism of Phenylalanine Phe – one of essential amino acids Must be included in our diet phenylalanine hydroxylase converts phenylalanine into tyrosine Tyrosin involved in other metabolic pathways

Chemistry link: phenylketonuria Babies born without phenylalanine hydroxylase Genetic disorder – phenylketonuria level of phenylalanine builds up - transaminated to phenylpyruvate (found in urine) In USA - tested for high serum phenylalanine levels immediately after birth High levels present - diet low in phenylalanine and high in tyrosine phenylalanine level is kept under careful control for the first 5 to 10 years of life, the child will experience no adverse effects

If the diet is not controlled - the baby will be severely mentally retarded by the time he or she is a few months old Untreated children - cannot synthesize melanin Half of untreated children - dead by age 20

Chemistry link: Alcaptnouria Genetic disease results from a deficiency of an enzyme in the pathway for phenylalanine degradation Caused by lack of homogentisate dioxygenase only ill effect – black urine Homogentisate they excrete immediately oxidizes in the air – forming a black compound

Anabolism Reverse of catabolism acetyl-CoA, pyruvate, and citric acid cycle intermediates are the starting materials For the synthesis of: fatty acids, monosaccharides, and amino acids compounds are then used to form fats, carbohydrates, and proteins

Problems Indicate whether an anabolic pathway or a catabolic pathway does the following: a. produces energy in the form of ATP b. involves primarily oxidation reactions

Summary Metabolism Anabolism Catabolism Catabolism of fats Catabolism of proteins Catabolism of carbohydrates

Structure of atom Chemical bonds PSE Isotopes Electronic configuration Formal charge Electronegativity Bond polarity Sigma bond Pi bond MO theory Bonding/antibonding orbitals Hybridization and molecular shapes Conjugated Pi-bonds Aromaticity Non covalent interactions Dipole moments Boiling point and branching Solubility Acids and bases pH and pKa Resonance contributor Resonance hybrid Predicting stability Delocalized electrons/energy UV/Vis Conjugated Pi-bonds and λmax Chirality Stereoisomers Asymmetric C atom Assigning priorities R or S isomer? SN1 and SN2 mechanisms Application in enzyme catalysis IR spectroscopy Parts of IR spectrum (alcohols, amines, fingerprint region etc.) Mass spectrometry Parts of MS spectrum (base peak etc.) Coupling GC/MS Structure of amino acids Zwitterion Isoelectric point Synthesis of amino acids Determination of amino acids Solution phase peptide synthesis Solid phase peptide synthesis Levels of protein structure Anabolism and catabolism Catabolism of fats, proteins and carbs Fates of pyruvate Stages of digestion Enzymes Coenzymes Vitamins Water and fat soluble vitamins Importance and deficiency of vitamins