“Organic Chemistry” revision

A. Medicinal Chemistry is rooted in organic chemistry – the study of organic (carbon-based) compounds. These compounds are classified by functional group – a group of atoms that occurs in many molecules & confers on them a characteristic chemical reactivity, regardless of the carbon skeleton. Functional groups are part of the overall structure of the drug & determine such characteristics as water or lipid solubility, reactivity, chemical stability, & in vivo stability, which in turn determine drug properties.

1. 1.        Functional groups can impart hydrophilic or lipophilic characteristics to a compound & thus affect a drug’s tendency to cross cellular membranes through passive diffusion.
2. 2.        Functional group reactivity is most important for reactions occurring under normal environmental conditions, primarily air oxidation & hydrolysis. E.g., benzene’s characteristic reactions occur only with special reagents & under special laboratory conditions. Thus, benzene’s shelf life is relatively long, & it requires no special storage conditions.
3. 3.        Functional groups affect drug reactivity &, hence, drug shelf life & stability.
4. 4.       Functional groups affect in vivo stability & duration of action – the susceptibility of the drug to biotransformation e.g. oxidation, reduction, & hydrolysis by metabolic enzymes.

B. Alkanes: (paraffins or saturated hydrocarbons)

• Have a general formula of R-CH₂-CH₃, where R is a radical or molecule fragment.
• Alkanes are lipid soluble.
• Common reactions: are halogenation & combustion.
• On the shelf, alkanes are chemically inert with regard to air, light, heat, acids, & bases.
• In vivo, alkanes are stable; terminal carbon or side-chain hydroxylation may occur.

C. Alkenes:  (olefins or unsaturated hydrocarbons)

• Have a general formula of R-CH=CH-R (characterized by the presence of the double bond).
• Lipid soluble, water insoluble, insoluble in aqueous acids or alkalies.
• Common reactions are: addition of hydrogen (reduction) or halogens, hydration (à glycols), & oxidation (à peroxides).
• On the shelf, volatile alkenes & peroxides may explode in presence of O₂ & a spark.
• In vivo, alkenes are relatively stable. Hydration, epoxidation, peroxidation, or reduction may occur.

1. What is the IUPAC name of the shown compound 2-methyl, 4-isopropyl, 2-hexene 2,5-dimethyl, 3-ethyl, 2-hexene 2,5-dimethyl, 4-ethyl, 2-hexene  5-methyl, 3(2-propyl), hex-4-ene 1,1,4-trimethyl, 3-ethyl, 1-pentene	CH2CH3      CH3 – C = CH – CH – CH – CH3                 CH3                             CH3
2. In which of the following systems would the above shown compound dissolve? a.    Water                                             c.     aqueous NaOH b.    Aqueous HCl                                d.      Decane (Octane, Acetone)

3. What type of chemical instability (in-vitro) might be predicted for this compound?

Chemically non reactive Peroxide formation Addition of H2O across the double bond Epoxidation

D. Alkyl Halides: (halogenated hydrocarbons)

• Have a general formula of R-CH₂-X.
• Lipid soluble (solubility increases with the extent of halogenation).
• Common reactions are: nucleophilic substitution & dehydro-halogenation.
• On the shelf, alkyl halides are stable.
• In vivo, alkyl halides are not readily metabolized.

E. Alcohols:

• Characterized by the presence of a hydroxyl group (– OH)
• May be classified as 1ry, 2ry, or 3ry alcohols (Figure 8-1).
• Low m wt alcohols are water soluble; water solubility decreases as HC chain length increases.
• Alcohols are also lipid soluble.
• Common reactions are: esterification & oxidation.
  • 1ry alcohols are oxidized to aldehydes & then to acids.
  • 2ry alcohols are oxidized to ketones.
  • 3ry alcohols ordinarily are not oxidized (as it contains no hydrogen).
• On the shelf, alcohols are stable.
• In vivo, alcohols may undergo oxidation, glucuronidation, or sulfation.

1. Which of the alcohols in the compound shown is a 3ry alcohol? a.   Alcohol (1)                c.   Alcohol (3) b.   Alcohol (2)                d.   Alcohol (4)
2. What properties would you predict for this compound? a.   Inflammable                c.   Soluble in water b.   Insoluble in water       d.   Soluble in aq. solutions
3. What type of instability would be expected for the alcohol portion of the molecule in presence of an oxidizing agent? Alcohols 2,3,4 would be oxidized to carboxylic acid. Alcohol 2 is stable & alcohols 3 & 4 oxidized to ketones Alcohol 2 is stable, alcohol 3 oxidized to acid & 4 to ketone All functional gps are stable to oxidizing agents
4. What type of chemical bonds is possible between water & the compound shown? Van der Waal bonds Hydrogen bonds Ion-dipole bonds Dipole-dipole bonds
5. Predict the solubility of the compound in the media given. Choose 1 for soluble, 5 for insoluble. Water Aqueous H2SO4 Aqueous KOH

5. In this compound, which alcohol is easily oxidized to COOH?

1. OH number 1                                         c.   OH number 2
2. OH number 3    (1ry alcohol)               d.   OH number 4 

 

F. Aromatic Hydrocarbons:  

• Are based on benzene (Figure 8-2).
• These molecules exhibit multi-centre bonding, which confers unique chemical properties.
• Lipid soluble.
• Common reactions: electrophilic aromatic substitution e.g. halogenation, nitration, sulfonation, & friedel craft’s alkylation.
• Benzene & related compounds (naphthalene) are planar molecules in the form of a regular hexagon.
• On the shelf, aromatic hydrocarbons are stable.
• In vivo, aromatic hydrocarbons undergo hydroxylation, epoxidation, & diol formation.

G. Phenols:

• Are aromatic compounds containing an OH group directly connecting to the aromatic ring.
• Monophenols have one OH group, & catechols have 2 OH groups next to each other (Figure 8-3).
• Lipid soluble; phenol itself (carbolic acid) is fairly water soluble. Ring substitutions generally decrease water solubility.
• Common reactions are: being acidic compounds they undergo all reactions of acids including: reactions with strong bases to form phenoxide ion (water soluble), esterification with acids, & oxidation (to form quinones, usually coloured).
• On the shelf, phenols are susceptible to air oxidation & to oxidation on contact with ferric ions.
• In vivo, phenols undergo sulfation, glucuronidation, aromatic hydroxylation, & O-methylation.

H. Ethers:

• Have a general formula of R-O-R, with an oxygen atom bonded to 2 carbon atoms.
• Low m wt ethers are partially water soluble; water solubility decreases with an increase in the HC portion of the molecule.
• Ethers are also lipid soluble.
• The common reaction of ethers is oxidation (to form peroxides).
• On the shelf, peroxides may explode.
• In vivo, ethers undergo O-dealkylation. Stability increases with the size of the alkyl group.

1. Would you predict the compound shown to be soluble in Water           (yes)          (no) Aq. HCl       (yes)          (no)
2. What in vitro instability may be expected from the compound shown above? Peroxidation (peroxide formation) in presence of air Oxidation with strong oxidizing agent Oxidation in presence of air Hydrolysis Stable

I. Aldehydes:

• Have a general formula of R-CHO & contain a carbonyl group (C=O).
• Lipid soluble. Low m wt aldehydes are also water soluble.
• Common reactions are: oxidation (to acids), reduction (to alcohols), hemiacetal & acetal formation.
• Low m wt aldehydes undergo polymerization.
• On the shelf, aldehydes oxidize to acids.
• In vivo, aldehydes may undergo oxidation to acids; aromatic aldehydes may undergo hydroxylation of aromatic group.

1. What is the IUPAC name of the shown compound? b-methyl, b-phenyl, g-oxopentanal 3-methyl, 4-oxo, 3-phenyl pentanal 3-methyl, 3-phenyl, 5-oxo, 2-pentanone 3-methyl, 3-acetyl phenyl, acetaldehyde
2. Predict the in vitro instability of the compound shown Oxidation of the ketone Oxidation of the aldehyde to acid Alkyl oxidation Aromatic Oxidation Peroxide formation
3. Predict the in vivo instability of the compound shown. Conjugation Aromatic hydroxylation Oxidation of the aldehyde Ketone oxidation Stable

J. Ketones:

• Have a general formula of R-CO-R [similar to aldehydes, contain a carbonyl group (C=O)].
• Lipid soluble.
• Low m wt ketones are also water soluble (solubility decreases as HC portion of molecule increases)
• Ketones are relatively non-reactive, although they may exist in equilibrium with their enol forms.
• On the shelf, ketones are very stable.
• In vivo, ketones may undergo some oxidation & some reduction.

1. The compound shown is soluble in      a.   Water                    d. All of the above      b.   Aq. HCl                e. None of the above      c.   Aq. NaOH
2. Predict the in vitro instability of the compound. Unstable in aq. acids due to ester hydrolysis Unstable in aq. bases due to amide hydrolysis	Unstable in aq. acids due to amide hydrolysis Unstable in aq. bases due to ester hydrolysis

 

K. Amines:

• Contain an amino group (–NH₂) which can exist in ionized or un-ionized form.
• The general formulas of 1ry, 2ry, 3ry & 4ry amines are shown in Figure 8-4 (note the no of H).
• Low m wt amines are water soluble; solubility decreases with increased branching (1ry amines are more water soluble than 2ry). However, 4ry amines (being ionic) & most amine salts are water soluble.
• Amines are also lipid soluble.
• Common reactions are: oxidation &, for alkyl amines, salt formation with acids.
• Aromatic amines, which are less basic, have less tendency to react with acids.
• On the shelf, phenolic amines are susceptible to air oxidation.
• In vivo, amines may undergo minor glucuronidation, sulfation, & methylation.
  • 1ry amines undergo oxidative deamination (removal of H & N with the formation of oxide).
  • 1ry & 2ry amines undergo acetylation.
  • 2ry & 3ry amines undergo N-dealkylation
  • 3ry amines undergo N-oxidation but are generally more stable than 1ry or 2ry amines.

1. Which nitrogen in the compound shown is a 3ry amine?
2. Which nitrogen in the compound shown is most basic?
3. Which nitrogen in the compound shown is least basic?
4. Which type of metabolism is possible at nitrogen (3)?      a.   Deamination                c.   Sulfate conjugation             e.   Stable, no metabolism      b.   Methylation                 d.   Glucouronide conjugation

L. Carboxylic Acids:

• Have a general formula: R-COOH.
• Low m wt carboxylic acids are water soluble, as are Na & K salts.
• Carboxylic acids are also lipid soluble.
• Common reactions are: salt formation with bases, esterification & decarboxylation.
• On the shelf, carboxylic acids are very stable.
• In vivo, carboxylic acids undergo conjugation (with glucuronic acid, glycine & glutamine) &        b-oxidation.

1. In the compound shown, which acid is the most acidic?
2. In the compound shown, which acid is the least acidic?
3. In the compound shown, which organic acid is the most acidic?
4. Which type of metabolism is expected for functional group (2)?      a.   Sulfate conjugation                      c.   Methylation                    e.   Glutamine conjugation      b.   Glucouronide conjugation        d.   Hydrolysis

M. Esters:

• Have a general formula of R-COOR.
• Lipid soluble;
• Low m wt esters are slightly water soluble.
• Common reaction is: hydrolysis to form carboxylic acid & alcohol.
• On the shelf, simple or low m wt esters are susceptible to hydrolysis, whereas complex, high m wt, or water-insoluble esters are resistant.
• In vivo, esters undergo enzymatic hydrolysis by esterases.

N. Amides:

• Have a general formula of R-CONH₂ or R-CONR-R (lactam form).
• Lipid soluble
• Low m wt amides are fairly water soluble.
• Amides have no common reactions.
• On the shelf, amides are very stable.
• In vivo, amides undergo enzymatic hydrolysis by amidases (with the formation of NH₃ & acid) primarily in the liver.

1. Which of the compounds shown contains carbamate?
2. What metabolism is expected for compound I ?     a.   Hydrolysis by esterases.               c.   N-dealkylation.                  e.   Fairly stable.     b.   Hydrolysis by amidases.              d.   Conjugation with sulphuric or glucouronic acid
3. What metabolism is expected for compound III ?     a.   Hydrolysis by esterases.            c.   Peroxide formation.               b.   Hydrolysis by amidases.              d.   Conjugation with sulphuric or glucouronic acid
4. The compound shown is soluble in aq NaOH because of salt formation at which functional gp?
5. The compound shown is soluble in HCl because of salt formation at which functional gp?
6. Predict the metabolism at position (1).     a.   Oxidation                    c.   Deamination                    e.   Stable     b.   Reduction                   d.   Conjugation
7. Predict the metabolism at position (2).     a.   Oxidation                    c.   Deamination                    e.   Stable     b.   Reduction                   d.   Conjugation

BIOCHEMISTRY

A. Introduction:

Biochemistry is the study of chemical principles that support life processes. It influences drug metabolism, therapeutic effectiveness & biotransformation. Biochemically significant molecules include amino acids & proteins, carbohydrates, lipids, pyrimidines & purines, & biopolymers (enzymes built from amino acids; polysaccharides built from carbohydrates; & nucleic acids built from pyrimidines & purines).

B. Amino Acids & Proteins:

1. 1.        Amino acids are the monomeric units of proteins & have the following general formula:

R – CH (NH₂) – COOH

1. Naturally occurring amino acids are mostly L, a-amino acids. Proteins are made up of the 20 different amino acids, which differ in the side chain (R) attached to the a-carbon. The 20 different side chains vary in size, shape, charge, hydrogen bonding capacity & chemical reactivity. A protein can be hydrolyzed into its component a-amino acids by acids, bases, or enzymes.
2. Amino acids have a zwitterion structure (both +ve & -ve regions of charge), which accounts for their high melting point & low water solubility. Amino acids in solution have the following general formula:                        R-CH-COO ^–  

    NH₃⁺

1. Ionization of amino acids to the zwitterion form or other forms depends on pH (Figure 8-5).
2. Amino acids are linked to form proteins by the peptide bond – a link between the carbonyl carbon & the amino nitrogen (Figure 8-6).
3. 2.       Proteins, (resulting from amino acids linking by peptide bonds) have 4 levels of structure.
   1. Primary structure refers to the sequence of amino acids & location of disulfide bond in the protein.
   2. Secondary structure refers to the spatial arrangement of sequenced amino acids; e.g., a-conformation (helical coil) or b-conformation (pleated sheet).
   3. Tertiary structure refers to the 3-dimensional structure of a single protein.
   4. Quaternary structure refers to arrangement of individual subunit chains into complex molecules.

C. Carbohydrates: These are polyhydroxy aldehydes or ketones. 3 major classes of carbohydrates exist.

1. 1.       Monosaccharides as glucose or fructose, consist of a single polyhydroxy aldehyde or ketone unit.
   1. Aldehydic monosaccharides are reducing sugars.
   2. Monosaccharides can be linked together by glycosidic bonds, which are hydrolyzed by acids but not by bases.
2. 2.       Oligosaccharides: consist of short chains of monosaccharides joined covalently.
   1. Sucrose cannot be absorbed in intestine unless converted by sucrase into glucose & fructose.
   2. Maltose is hydrolyzed by maltase into two molecules of glucose.
   3. Lactose (milk sugar) cannot be absorbed unless converted by lactase into galactose & glucose.
3. 3.        Polysaccharides, such as cellulose & glycogen, consist of long chains of monosaccharides.

D. Pyrimidines & Purines: are bases that, when bonded with ribose, form nucleosides, which when subsequently bonded to phosphoric acid form nucleotides (structural building blocks of nucleic acids).

1. 1.       Pyrimidine bases include:
   1. Cytosine (C), found in deoxyribonucleic acid (DNA) & ribonucleic acid (RNA)
   2. Uracil (U), found in RNA only
   3. Thymine (T), found in DNA only
2. 2.       Purine bases include:
   1. Adenine (A), found in DNA and RNA
   2. Guanine (G), found in DNA and RNA
3. 3.        Pyrimidines & purines exhibit tautomerism (a form of stereoisomerism) & can exist in either keto (lactam) or enol (lactim) forms.

E. Biopolymers

1. 1.        Enzymes: are proteins capable of acting as catalysts for biologic reactions. They may be simple or complex & may require cofactors or coenzymes for biologic activity.
   1. An enzyme enhances the rate of a specific chemical reaction by lowering the activation energy of the reaction. It does not change the reaction’s equilibrium point, & it is not used up or permanently changed by the reaction.
   2. A cofactor may be an inorganic component (a metal ion) or a non-protein organic molecule. It may be biologically inactive without an apoenzyme (the protein portion of a complex enzyme). A cofactor firmly bound to the apoenzyme is called a prosthetic group. An organic cofactor that is not firmly bound but is actively involved during catalysis is called a coenzyme.
   3. A complete, catalytically active enzyme system is referred to as a holoenzyme.
   4. Enzymes fall into six major classes.

• Oxidoreductases (dehydrogenases, oxidases, peroxidases): important in oxidative metabolism.
• Transferases catalyze the transfer of groups, e.g. phosphate & amino groups.
• Hydrolases (proteolytic enzymes, amylases, esterases) hydrolyze their substrates.
• Lyases (decarboxylases, deaminases) catalyze removal of functional groups by means other than hydrolysis.
• Ligases (DNA ligase, which binds nucleotides together during DNA synthesis) catalyze the coupling of 2 molecules.
• Isomerases catalyze various isomerizations, as the change from D to L forms or the change from cis- to trans-isomers.

1. 2.        Polysaccharides (also called glycans) are long-chain polymers of carbohydrates & may be linear or branched. They are classified as homopolysaccharides or heteropolysaccharides.
   1. Homopolysaccharides (e.g., starch, glycogen, cellulose) contain only one type of monomeric unit.

• Starch: is composed of 2 glucose polymers – amylose (linear & water soluble) & amylopectin (highly branched & water insoluble). It yields maltose (glucose disaccharide) after enzymatic hydrolysis by salivary or pancreatic amylase; only glucose after complete hydrolysis by strong acids.
• Glycogen, like amylopectin, is a highly branched, compact chain of D-glucose. The main storage polysaccharide of animal cells, it is found mostly in liver & muscle & can be hydrolyzed by salivary or pancreatic amylase into maltose & D-glucose.
• Cellulose (a water-insoluble structural polysaccharide found in plant cell walls) is a linear, unbranched chain of D-glucose. It cannot be digested by humans because the human intestinal tract secretes no enzyme capable of hydrolyzing it.

1. Heteropolysaccharides (e.g., heparin, hyaluronic acid) contain 2 or more types of monomeric unit.

• Heparin (an acid mucopolysaccharide) consists of sulfate derivatives of N-acetyl-D- glucosamine & D-iduronate. It can be isolated from lung tissue & is used medically to prevent blood clot formation.
• Hyaluronic acid, a component of bacterial cell walls as well as of the vitreous humor & synovial fluid, consists of alternating units of N-acetyl-D-glucosamine & N-acetyl-muramic acid.

1. 3.       Nucleic acids are linear polymers of nucleotides – pyrimidine & purine bases linked to ribose or deoxyribose sugars (nucleosides) & bound to phosphate groups. The backbone of the nucleic acid consists of alternating phosphate & pentose units with a purine or pyrimidine base attached to each.
   1. Nucleic acids are strong acids, closely associated with cellular cations & such basic proteins as histones & protamines.
   2. The 2 main types of nucleic acids are DNA and RNA. RNA exists in 3 forms.

• Ribosomal RNA (rRNA) is found in ribosomes, but its functions are not fully understood yet.
• Messenger RNA (mRNA) serves as the template for protein synthesis & specifies a polypeptide’s amino acid sequence.
• Transfer RNA (tRNA) carries activated amino acids to the ribosomes, where the amino acids are incorporated into the growing polypeptide chain.

1. In both DNA & RNA, the successive nucleotides are joined by phosphodiester bonds between the 5′-hydroxy gp of one nucleotide’s pentose & the 3′-hydroxy gp of the next nucleotide’s pentose.
2. DNA differs from RNA in that it lacks a hydroxyl group at the pentose’s C₂’ position, & it contains T rather than U.
3. DNA structure consists of 2 a-helical DNA strands coiled around same axis to form a double helix. The strands are antiparallel-the 5′, 3′-internucleotide phosphodiester links run in opposite directions.

• Hydrogen bonding between specific base pairs A-T & cytosine (C)-G holds the 2 DNA strands together. The strands are complementary (the base sequence of one strand determines the base sequence of the other).
• The hydrophobic bases are on the inside of the helix; the hydrophilic deoxyribose-phosphate backbone is on the outside.

 

 

BIOCHEMICAL METABOLISM

A. Overview: Biochemical metabolism is the review of pathways that lead to the synthesis or breakdown of compounds important to the life of an organism.

1. 1.       Control of metabolism: Metabolism is controlled by substrate concentration, enzymes (constitutive or induced), allosteric (regulatory) enzymes, hormones, & compartmentation.
2. 2.       Catabolism is the sum of degradation reactions that usually release energy for useful work (e.g., mechanical, osmotic, biosynthetic).
3. 3.       Anabolism is the sum of biosynthetic (build-up) reactions that consume energy to form new biochemical compounds (metabolites).
4. 4.        Amphibolic pathways are those that may be used for both catabolic as well as anabolic purposes. Krebs cycle breaks down metabolites primarily to release 90% of the total energy of an organism. It also draws off metabolites to form compounds e.g. amino acids (aspartic, glutamic, alanine). Hemoglobin has its heme moiety formed from succinyl coenzyme A (succinyl CoA) & glycine followed by a complex set of reactions.

B. Bioenergetics

1. 1.        Substrate level phosphorylation entails the formation of one unit of A tri-phosphate (ATP) per unit of metabolite transformed (e.g., succinyl CoA to succinate, phosphoenolpyruvate to pyruvate). These reactions do not need oxygen.
2. 2.        Oxidative phosphorylation entails the formation of 2 or 3 units of ATP per unit of metabolite transformed by oxidoreductase enzymes (e.g., dehydrogenases); these enzymes use flavin A dinucleotide (FAD) formed from the vitamin riboflavin, or nicotinamide A dinucleotide (NAD⁺) from the vitamin nicotinamide as cofactors. The reactions are coupled to the electron transport system, & the energy released is used to form ATP in the mitochondria.

C. Carbohydrate Metabolism

1. 1.       Catabolism. This process releases stored energy from carbohydrates.
   1. Glycogenolysis is the breakdown of glycogen into glucose phosphate in the liver & skeletal muscle, controlled by the hormones glucagon & epinephrine.
   2. Glycolysis is the breakdown of sugar phosphates (glucose, fructose, glycerol) into pyruvate (aerobically) or lactate (anaerobically).
2. 2.       Anabolism. This process consumes energy to build up complex molecules from simpler molecules.
   1. Glycogenesis is the formation of glycogen in the liver & muscles from glucose consumed in the diet; its synthesis is controlled by the pancreatic hormone insulin.
   2. Gluconeogenesis is the formation of glucose from non-carbohydrate sources, such as lactate, alanine, pyruvate, & Krebs cycle metabolites; fatty acids cannot form glucose.

 

 

D. Krebs Cycle: This pathway serves both breakdown & synthetic purposes & occurs in the mitochondrial compartment.

1. 1.        Catabolism. This pathway converts pyruvate (glycolysis), acetyl CoA (fatty acid degradation), & amino acids to CO₂ & water with a release of energy. The cycle is strictly oxygen-dependent (aerobic). Mature RBCs lack mitochondria; hence, there is no Krebs cycle activity.
2. 2.        Anabolism. This pathway forms amino acids as aspartate & glutamate from cycle intermediates; also, the porphyrin ring of heme (hemoglobin, myoglobin, cytochromes) is formed from a cyc1e intermediate.
3. 3.        Anaplerotic reactions. Because metabolites are used to make amino acids or heme (e.g., succinyl CoA), the metabolite must be replaced by intermediates from other sources (e.g., glutamate from the breakdown of protein forms ketoglutarate).
4. 4.        Electron transport. The electron transport system accepts electrons & hydrogen from the oxidation of Krebs cycle metabolites & couples the energy released to synthesize ATP in the mitochondria.

E. Lipid Metabolism

1. 1.       Catabolism. Triglicerides (triacylglycerols) stored in fat cells (adipocytes) are hydrolyzed by hormone-sensitive lipases into three fatty acids & glycerol.
   1. Fatty acids are broken down by beta oxidation to acetyl CoA (2 carbon units), which – enter the Krebs cycle to complete the oxidation to CO₂ & water with release of considerable energy. Too rapid breakdown of fatty acids leads to ketone bodies (ketogenesis) as in diabetes mellitus.
   2. Glycerol enters glycolysis & is oxidized to pyruvate &, via the Krebs cycle, to CO₂ & water.
   3. Steroids may be converted to other compounds such as bile acids, vitamin D, or steroidal hormones (e.g., cortisone, estrogens, androgens); they are not broken down completely.
2. 2.        Anabolism. Biosynthesis forms fatty acids, steroids, & other terpene-related metabolites.
   1. Fatty acids are formed in the cytoplasm, & unsaturation occurs in the mitochondria or endoplasmic reticulum. Humans cannot make linoleic acid; thus, it is important that it be included in the diet (essential fatty acid).
   2. Terpene compounds are derived from acetyl CoA via mevalonate & include:

• Cholesterol and other steroids
• Fat-soluble vitamins (i.e., A, D, E, K)
• Bile acids

1. Sphingolipids contain sphingenine formed from palmitoyl CoA & serine. Sphingenine forms a ceramide backbone when joined to fatty acids. The addition of sugars, sialic acid, or choline phosphate forms compounds such as cerebrosides, gangliosides, or sphingomyelin found in nerve tissues & membranes.
2. Phosphatidyl compounds, such as phosphatidyl choline (lecithin), phosphatidyl serine, or ethanolamine, are also important parts of membranes.

 

F. Nitrogen Metabolism: Nitrogen metabolism involves amino acid metabolism & nucleic acid metabolism (see Chapter 9 for a discussion of the nucleic acid role in cell activity).

1. 1.       Catabolism
   1. Amino acids. The amino group is removed by a transaminase enzyme. The carbon skeleton is broken down to acetyl CoA (ketogenic amino acids) or to citric acid cycle intermediates (glycogenic amino acids) & oxidized to CO₂ & water for energy. Glycogenic amino acids form glucose as needed via gluconeogenesis; some amino acids are both ketogenic & glycogenic (e.g., tyrosine).
   2. Purines are salvaged (90%), & the remaining 10% are degraded in a sequence that includes xanthine oxidase forming uric acid in humans.
   3. Pyrimidines are catabolized to b-alanine, ammonia, & carbon dioxide.
2. 2.       Anabolism
   1. Amino acids are formed from the citric acid cycle intermediates (see III D 2); others must be eaten daily in dietary proteins. The latter are called essential amino acids [phenylalanine, valine, tryptophan (PVT); threonine, isoleucine, methionine (TIM); histidine, arginine in infants, lysine, leucine (HALL)].
   2. Purines are formed by complex reactions using carbamoyl phosphate, aspartate, glutamine, glycine, CO₂, and formyl tetrahydrofolate.
   3. Pyrimidines are formed from aspartate & carbamoyl phosphate in a multistep process.

G. Nitrogen Excretion: Excess nitrogen must be eliminated because it is toxic. Humans primarily excrete urea but also excrete uric acid.

1. 1.        Urea synthesis. The Krebs-Henseleit pathway is used to form urea principally in the liver. The ammonia is removed from amino acids by amino acid transferases (transaminases) that use pyridoxal phosphate (vitamin B₆) as a coenzyme. Glutamine is formed from glutamate (an intermediate) & ammonia; glutamine & CO₂ form carbamoyl phosphate, which enters the urea cycle & after several steps forms urea.
2. 2.       Uric acid synthesis. Although most purines are salvaged, humans excrete the remaining purines as uric acid.