2: Biochemistry and Physiology

2 Biochemistry and Physiology

KENNETH R. ETZEL

OUTLINE

1. BIOLOGICAL COMPOUNDS
2. METABOLISM
3. MOLECULAR AND CELLULAR BIOLOGY
4. CONNECTIVE TISSUE AND BONE
5. MEMBRANES
6. NERVOUS SYSTEM
7. MUSCLE
8. CIRCULATION
9. RESPIRATION
10. RENAL
11. ORAL PHYSIOLOGY
12. DIGESTION
13. ENDOCRINES

1.0 BIOLOGICAL COMPOUNDS

Biological systems depend upon molecules that serve various functions. They may serve as structural components, regulatory agents, energy sources, enzymatic agents, osmotic regulators, transport agents, and agents of hereditary information. Each of these compounds has unique characteristics that enable them to perform their function in both the intracellular and extracellular environments. This section will focus on these biochemical agents and relate their function to biological systems in which they participate.

1.1 Sugars and Carbohydrates

A. Carbohydrate terminology

1. Empirical formula (CH2O)n.
2. Classified based on the number of carbons.

a. Trioses (3)
b. Tetroses (4)
c. Pentoses (5)
d. Hexoses (6)

3. Aldoses—contain an aldehyde as their most oxidized functional group. Can contain any number of carbons.

a. Glyceraldehydes (aldotriose)
b. Glucose (aldohexose)

4. Ketoses—contain a keto group as their most oxidized functional group. Fructose is a ketohexose.
5. Isomers—the chemical formula is the same, but the structure is different.
6. Epimers—configuration around one carbon differs.
7. Glycosidic bonds—bonds formed between two sugars or a sugar and another noncarbohydrate molecule.

B. Carbohydrate classification—carbohydrates are classified based on the number of simple sugar units they contain. Examples are given in Figure 2-1.

1. Monosaccharides (glyceraldehydes, ribose, xylose, glucose, mannose, galactose, fructose).
2. Disaccharides (lactose, maltose, sucrose).
3. Oligosaccharides (often found in glycoprotein).
4. Polysaccharides.

a. Amylose—unbranched glucose chain of α(1,4) glycosidic bonds).
b. Amylopectin—α(1–4) glucose chains with branches of α(1,6) glycosidic bonds).
c. Glycogen—α(1–4) glucose chains with highly branched α(1,6) glycosidic bonds, which is the principal carbohydrate storage molecule in vertebrates.
d. Cellulose—polymer of glucopyranose linked by β (1,4) glycosidic bonds. Major structural polysaccharide in plants.
e. Mucopolysaccharidoses are hereditary disorders (deficiency of lysosomal hydrolases, which degrade heparin sulfate or dermatan sulfate), which result in the accumulation of glycosaminoglycans in tissues.

C. Function of carbohydrates

1. Important source of energy.
2. Component of RNA and DNA.
3. Structural component of plants and animals.

D. Nutritional implications of carbohydrates

1. Monosaccharides are absorbed by a secondary active transport system (Na+ and sugar cotransported) or facilitated diffusion.
2. Disaccharides are absorbed by secondary active transport followed by digestion by brush border enzymes (lactase, maltase, sucrase).
3. Polysaccharides are digested by amylase secreted by the salivary glands and pancreas.
4. Refer to the metabolism section for discussion of regulation of blood glucose and glycogen metabolism.

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Figure 2-1 Chemical structures of glucose and lactose.

1.2 Amino Acids and Proteins

A. Protein terminology

1. Amino acids—building blocks of proteins consisting of a carboxyl group, an amino group, and a distinctive side chain attached to the α carbon. Depending on the side chain, each amino acid has specific characteristics (Figure 2-2).

a. Nonpolar side chains (glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, and proline). These promote hydrophobic interactions.
b. Uncharged polar side chains (asparagine, cysteine, glutamine, tyrosine, threonine, serine). These have no charge at neutral pH but may participate in hydrogen bond formation with other compounds.
c. Acidic side chains (aspartic acid, glutamic acid). These have negative charges at neutral pH due to the charge on the carboxyl group.
d. Basic side chains (arginine, lysine, and histidine). Have positive charges at neutral pH due to the ability to accept protons.
e. Peptide bond—a covalent linkage that is formed between the free amino end of the peptide or amino acid and the free carboxyl end of the peptide or amino acid. It is responsible for the formation of the primary structure of a protein.
2. Characteristics of weak acids and weak bases. The Henderson-Hasselbalch equation describes the relationship between pK and pH. Can be used to determine the dissociation of ionizable groups at a given pH.

a. pH = −log [H+].
b. pK of an acid is defined as the pH at which the acid is half-dissociated. pK = −log K.
c. Hydrogen bond—responsible for the secondary structure of proteins. Formed through interactions of the carbonyl oxygens and amide hydrogens that are a part of the peptide.

(1) α helix—coiled polypeptide core with amino acid side chains extending outward to avoid steric interference. Keratins and myoglobin are examples.
(2) β sheets—characterized by hydrogen bonds between two or more polypeptide chains.

d. Tertiary structure—the three-dimensional structure of a protein due to side chain interactions of the peptide. May be due to hydrophobic or hydrophilic interactions, hydrogen binding, disulfide bonds, or ionic interactions.
e. Hydrophilic groups—amino acids that are found on the surface of the molecule. Responsible for tertiary structure of proteins.
f. Hydrophobic groups—amino acids that are found in the interior of the molecule. Responsible for tertiary structure of proteins.
g. Disulfide bonds—a covalent link between cysteine groups, which results in a folding of the primary structure. Also responsible for the tertiary structure of protein.
h. Protein misfolding is associated with a number of diseases (amyloidoses), including Alzheimer disease and bovine spongiform encephalopathy (mad cow disease).
i. Hemoglobinopathies are disorders produced by abnormal hemoglobin molecules or insufficient amounts of the globular protein. Examples include sickle cell anemia (abnormal β chain of the globulin molecule) and thalassemia (imbalance of α and β chains).

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Figure 2-2 Chemical structures of three amino acids.

1.3 Lipids

A. Lipid terminology

1. Fatty acids are straight-chained compounds containing an even number of hydrocarbons. They possess a terminal carboxyl group that provides polarity to the molecule. Because of this characteristic, fatty acids are amphipathic (contain both hydrophilic and hydrophobic moieties).

a. Saturated fatty acid—contains no double bonds.
b. Unsaturated fatty acid—contains double bonds that are identified with δ or ω terminology. May be either monounsaturated or polyunsaturated.
c. Triacylglycerols (triglycerides)—esters of glycerol and three fatty acids. These are hydrophobic since the carboxyl group is covalently linked to glycerol.

2. Essential fatty acids cannot be synthesized in the body.

a. Linoleic acid.
b. Linolenic acid.
c. Arachidonic acid (if linoleic acid is missing from the diet).

3. Lipoproteins—a complex consisting of a hydrophobic core surrounded by a hydrophilic shell. Serves as a vehicle for transporting triacylglcerol and cholesterol in plasma. Based on density (protein content), they are classified into several categories (see Lipoproteins, B.3. below).
4. Cholesterol—characterized by a four-ring sterol ring, hydrocarbon (hydrophobic) tail, and hydroxyl (polar) site on the steroid nucleus.

B. Classification of lipids

1. Phospholipids—composed of glycerol or sphingosine, two fatty acids, and phosphoric acid. They are an important component of membranes since they have hydrophobic (fatty acid) and hydrophilic (phosphoric acid) domains. In an aqueous environment, they form bimolecular layers, which are the biological basis of membranes.

a. Phosphoglycerides—composed of glycerol, fatty acids, and phosphate.

(1) Phosphatidic acid (PA) is a common precursor of other phosphoglycerides.
(2) PA and serine = phosphatidylserine (important component of membranes).
(3) PA and ethanolamine = phosphatidylethanolamine or cephalin (important for mitochondrial activity).
(4) PA and choline = phosphatidylcholine or lecithin (major constituent of surfactant).
(5) Respiratory distress syndrome is caused by the inability to synthesize surfactant (dipalmitoyllecithin).
(6) PA and inositol = phosphatidylinositol (precursor of second messengers diacylglycerol and inositol trisphosphate) (Figure 2-3).
(7) PA and glycerol = phosphatidylglycerol.

b. Sphingophospholipids—composed of sphingosine, fatty acid, phosphoric acid, and choline. Sphingomyelin, a member of this group, is an important constituent of myelin.

2. Glycolipids (glycosphingolipids)—composed of carbohydrate, sphingosine, and fatty acid. These compounds are often found on plasma membrane surfaces, especially in nervous tissue. Gangliosides are members of this group and appear to have a role in receptor function.
3. Lipoproteins (found in plasma)

a. Chylomicron—composed primarily of dietary triacylglycerol.
b. Very-low-density lipoprotein (VLDL)—transports endogenous triacylglycerol from liver to cells.
c. Intermediate-density lipoprotein (IDL)—returns endogenous cholesterol to liver.
d. Low-density lipoprotein (LDL)—transports cholesterol from liver to cells.
e. High-density lipoprotein (HDL)—transports cholesterol from cells to IDL and LDL and back to the liver.

4. Apoproteins

a. Apo A required for cholesterol transport from peripheral tissue to the liver.
b. Apo B is required for binding of LDL to cell surface receptors.
c. Apo C regulates the activity of lipoprotein lipase.
d. Apo E is required for the removal of chylomicrons and IDL from plasma.

C. Function of lipids

1. Component of biological membranes (phospholipids and sphingolipids).
2. Facilitate the interactions between membrane proteins and hydrophobic environments in the membrane (a function, for instance, of covalent modification of the protein with myristic and palmitic acids).
3. Source of energy (triacylglycerol).
4. Provides insulation and protection (triacyglycerol).
5. Precursor of hormones and intracellular messengers (fatty acids).
6. Precursor of steroid hormones, bile acids and salts, membranes (cholesterol).

D. Nutritional implication of lipids

1. Essential fatty acids—cannot be synthesized by mammals and therefore must be obtained from the diet (linoleic and linolenic). Arachidonic acid is synthesized from linoleic acid. Arachidonic acid is a precursor of the eicosanoids, which function as hormone-like molecules in most tissues (Figure 2-4). Prostaglandins, thromboxanes, and leukotrienes are examples of these molecules. If linoleic acid is missing from the diet, arachidonic acid becomes essential.
2. Nonessential fatty acids—can be synthesized by enzyme systems in the body.
3. In general, the more saturated the fat, the more solid it is at room temperature.
4. Triacyglycerols release 9.3 kcal/g and therefore are an important source of energy.

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Figure 2-3 Structure of phosphatidylinositol, showing the inositol bound to the phosphate group, which is attached to the glycerol backbone. Two fatty acids, palmitic and linoleic (unsaturated), are shown in ester linkage to glycerol.

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Figure 2-4 Arachidonic acid is a precursor of the eicosanoids, which function as hormone-like molecules in most tissues.

(From Metzler DE: Biochemistry, ed 2, Academic Press, San Diego, 2003.)

1.4 Nucleic Acids and Metabolism

A. Nucleic acid terminology (Figure 2-5):

1. Nucleic acids—complex molecules that combine with several different classes of smaller molecules to form either deoxyribonucleic acid or ribonucleic acid.
2. Bases of nucleic acids

a. Purines (adenine and guanine).
b. Pyrimidines (cytosine, thymine, and uracil).

3. Nucleosides—compounds formed when either a purine or pyrimidine base is linked to a sugar molecule. Examples:

a. Adenine + ribose = adenosine.
b. Cytosine + deoxyribose = deoxycytidine.

4. Nucleotides—the molecule formed by linking phosphate groups to nucleosides. Examples:

a. Adenine + ribose + phosphate = adenosine monophosphate.
b. Cytosine + deoxyribose + phosphate = deoxycytidine monophosphate.

5. Adenonosine triphosphate (ATP)—high-energy nucleotide used as an energy source in numerous biological systems.
6. Polynucleotides—by removing a molecule of water between the phosphate group of one nucleotide and the sugar group of the other (phosphate–ester bond), a polynucleotide chain is formed. The chains formed are either polyribonucleotides (RNA) or polydeoxyribonucleotides (DNA).
7. Transcription—making RNA from DNA.
8. Translation—the production of a polypeptide using an mRNA template.
B. Classification of nucleic acids

1. DNA

a. Composed of four bases linked to deoxyribose and phosphate.

(1) Adenine
(2) Guanine
(3) Cytosine
(4) Thymine

b. Consists of two strands of nucleotides in the form of a double helix.
c. The double helix is held together by hydrogen bonds.
d. Only adenine and thymine and guanine and cytosine are paired. Thus, the two strands are said to be complementary.

2. RNA

a. Composed of four bases linked to ribose and phosphate.

(1) Adenine
(2) Guanine
(3) Cytosine
(4) Uracil

b. Types of RNA

(1) Ribosomal RNA (rRNA)—integral component of ribosomes, the site of protein synthesis.
(2) Messenger RNA (mRNA)—carries the genetic information of DNA to the site of protein synthesis.
(3) Transfer RNA (tRNA)—transfers amino acids to the site of protein synthesis.

C. Function of nucleic acids

1. DNA is responsible for transmitting genetic information from generation to generation.
2. RNA transmits the genetic information stored in DNA for the synthesis of proteins.

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Figure 2-5 Chemical structures of the purines, adenine, and guanine and pyrimidines, cytosine, thymine, and uracil. The structures of the nucleoside, adenosine, and the nucleotide, adenosine triphosphate, are also shown.

1.5 Nutrients and Minerals

A Vitamins—traditionally divided into fat and water-soluble vitamins. Vitamins A, D, K, and E are fat-soluble, and the remaining nine are water-soluble. Due to the ability of the fat-soluble vitamins to be retained in lipid throughout the body, the potential for toxicity is, in general, greater than that of the water-soluble vitamins.

1. Thiamin (B1)

a. Coenzyme form: thiamine pyrophosphate.
b. Involved in two key cell reactions: decarboxylation and transketolation.
c. Deficiency results in the impairment of carbohydrate metabolism and lipid biosynthesis. Beriberi is a disease of the peripheral nerves caused by thiamin deficiency.

2. Riboflavin (B2)

a. Coenzyme form: flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD).
b. Catalyzes important reactions in the respiratory chain of cellular energy metabolism.
c. Deficiency results in oral symptoms, including angular cheilosis and glossitis.

3. Nicotinamide (niacin)

a. Coenzyme form: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).
b. Participates in reversible oxidation-reduction reactions that are necessary for the utilization of all major nutrients.
c. Deficiency results in pellagra (dermatitis, diarrhea, and dementia). Oral symptoms are also possible.

4. Pantothenic acid

a. Coenzyme form: coenzyme A.
b. Involved in many reversible acetylation reactions in carbohydrate, fat, and amino acid metabolism.

5. Pyridoxine (B6)

a. Coenzyme form: pyridoxal phosphate.
b. Involved in a number of enzyme systems essential for normal amino acid metabolism.
c. Deficiency results in seborrheic dermatitis, cheilosis, glossitis, and stomatitis.

6. Biotin

a. Functions as a coenzyme involved in the process of carboxylation.
b. Works with acetyl CoA in reactions that transfer carbon dioxide from one compound to another.

7. Folic acid

a. Coenzyme form: tetrahydrofolate.
b. Plays a major role as an intermediate carrier of one-carbon units to appropriate metabolites in the synthesis of nucleic acids and porphyrin compounds.
c. Since folic acid is essential for normal cell division and replication, a deficiency will manifest itself in the most rapidly growing tissues such as in bone marrow and the gastrointestinal tract. Megaloblastic anemia is symptomatic of folic acid deficiency. Maternal deficiency is also associated with neural tube defects in pregnancy.

8. Cyanocobalamine (B12)

a. Coenzyme form: adenosyl cobalamine.
b. Plays a role in the transfer of single carbon intermediates (primarily methyl groups) from one compound to another.
c. Deficiency is often found in individuals who lack the normal intrinsic factor for the proper absorption of vitamin B12. This results in pernicious anemia characterized by a megaloblastic macrocytic anemia and progressive neurological degeneration.

9. Ascorbic acid (C)

a. Plays a role in the metabolism of amino acids, in particular the final oxidation of phenylalanine and tyrosine. Also essential for the normal elaboration of the intercellular substance of collagenous and fibrous tissue in animals. As a cofactor in the enzymatic hydroxylation of proline to 4-hydroxyproline, it is required for the formation and maintenance of bone matrix, cartilage, dentin, collagen, and connective tissue in general.
b. Deficiency results in scurvy, which exhibits symptoms related to connective tissue weakening.

10. Vitamin A

a. Vitamin A plays a role in maintaining the normal structure and function of biological membranes both as components of intracellular organelles or peripheral cell membranes. Epithelial cells also depend upon vitamin A for optimal growth and integrity. The vitamin is also essential for osteoblast and osteoclast activity.
b. Deficiency is associated with night blindness since retinol is limited and the amount of rhodopsin is decreased.
c. Can be synthesized from carotenoids in the diet. Preformed vitamin A is potentially very toxic.

11. Vitamin E

a. A generic name for a group of compounds with vitamin E activity, of which α-tocopheral is the most significant.
b. Plays a major role in protecting cellular and subcellular membranes from deterioration. As an antioxidant, vitamin E protects the polyunsaturated fatty acids in lipid membranes from oxidation.

12. Vitamin K

a. The major function of vitamin K is to catalyze the posttranslational modification of blood-clotting factors in the liver. These include four factors:

(1) Factor II, prothrombin.
(2) Factor VII, serum prothrombin conversion factor.
(3) Factor IX, plasma thromboplastin component.
(4) Factor X, Stuart factor.

b. Warfarin, a vitamin K analog, interferes with vitamin K activity.

13. Vitamin D

a. Cholesterol serves as the precursor for the synthesis of vitamin D3 (cholecalciferol). This step requires UV light.
b. Enzymes in the liver (25-hydroxylase) and kidney (1-hydroxylase) are required for the synthesis of the active 1,25 dihydroxycholecalciferol.
c. Vitamin D increases Ca2+ and Pi intestinal absorption and mobilization from bone.
d. Deficiency results in rickets (children) and osteomalacia (adults).

B. Minerals—in biological systems, minerals are often associated with enzymes, and they function as cofactors. The following are examples of cofactors (minerals) and the enzymes with which they are associated:

1. Fe2+ or Fe3+—cytochrome oxidase, catalase, peroxidase.
2. Cu2+—cytochrome oxidase.
3. Zn2+—DNA polymerase, carbonic anhydrase, alcohol dehydrogenase.
4. Mg2+—hexokinase, glucose-6-phosphatase.
5. Mn2+—arginase.
6. K+—pyruvate kinase.
7. Ni2+—urease.
8. Mo—nitrate reductase.
9. Se—glutathione peroxidase.

2.0 METABOLISM

2.1 Bioenergetics

The study of the energy transductions that occur in living cells and the chemical processes underlying these transductions.

A. Terminology

1. Entropy (δ S)—degree of randomness in a system.
2. Enthalpy (δ H)—heat change during a chemical reaction due to differences in bond energy.
3. Exergonic—the free energy of the products is lower than the free energy of the reactants (δ G < 0). (Net energy is released as a result of the reaction.)
4. Endergonic—the free energy of the products is higher than the free energy of the reactants (δ G > 0). (Net energy is consumed as a result of the reaction.)
5. Equilibrium constant (Keq)—the ratio of the concentration of products to reactants when the reaction reaches equilibrium. The larger the Keq, the more favorable the reaction.
6. Free energy (δ G)—the energy that can drive a chemical reaction.

a. Negative δ G—the reaction proceeds in the direction written.
b. Positive δ G—the reaction goes in the opposite direction.
c. δ G is 0—the reaction is at equilibrium.

7. Free energy of activation—energy required to reach the transition state.
8. Transition state—highest energy arrangement of the atoms that occurs between the reactants and the products.
9. Thermodynamics—the energy state of a system and the direction in which the reaction will proceed.
10. Kinetics—the rate of the reaction and the factors that affect the rate. The rate of the reaction can be increased in two ways:

a. Increase the temperature to activate more molecules to reach the transition state.
b. Lower the activation of energy of the transition state by using a catalyst.

2.2 Enzymology

Enzymes are biological compounds that catalyze chemical reactions. Enzymes can alter the rates of reactions but cannot alter the equilibrium of the reaction. Most enzymes are highly specific since they associate with substrates through specific sites in the catalytic center of the enzyme.

A. Classification of enzymes

1. Oxidoreductases—one substrate is oxidized, while at the same time, the other is reduced.
2. Transferases—transfer functional groups between two substrates.
3. Hydrolases—catalyze the hydrolysis of proteins, carbohydrates, and so forth.
4. Lyases—remove two groups from a substrate, leaving a double bond.
5. Isomerases—interconvert isomers.
6. Ligases—catalyze the formation of covalent bonds, utilizing the hydrolysis of ATP or some other high-energy compound.

B. Michaelis-Menten equation—examines the kinetics of enzyme catalyzed reactions.
C. Enzyme kinetics plot (velocity versus substrate) (Figure 2-6):

1. Vmax = maximum velocity of the reaction.
2. Km = the substrate concentration at which the velocity is 50% of the maximum velocity.
D. Enzyme inhibition—numerous substances (including drugs and metabolites) can interfere with enzyme activity. This inhibition may be reversible or irreversible. Three types of reversible inhibitory mechanisms can be identified by enzyme kinetic plots.

1. Competitive inhibition

a. Substances are similar to the substrate and therefore compete for binding at the active site.
b. Km is increased but there is no change in Vmax.

2. Uncompetitive inhibition

a. The inhibitor binds only to the substrate–enzyme complex.
b. Both the Vmax and Km are reduced.

3. Noncompetitive inhibition

a. The inhibitor can bind to the substrate-enzyme complex or free enzyme.
b. Vmax is decreased, but Km is unaffected.

E. Enzyme regulation can occur by the following mechanisms:

1. Increased synthesis of the enzyme.
2. Activation or inactivation by proteolytic enzymes.
3. Activation or inactivation by covalent modification (phosphorylation).
4. Allosteric modification.
5. Degradation of enzymes by proteases.

F. Measurement of enzymes is useful in the diagnosis of disease. For example, alanine aminotransferase (liver damage), creatine kinase, troponin T, and lactate dehydrogenase (myocardial infarction).
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Figure 2-6 Double-reciprocal or Lineweaver-Burk plot of 1/v versus 1/[S]. The intercept on the vertical axis gives 1/Vmax and the slope gives Km/Vmax. The intercept on the horizontal axis equals −1/Km.

(From Metzler DE: Biochemistry, ed 2, Academic Press, San Diego, 2003.)

2.3 Catabolism

The degradation of large complex molecules into smaller, simple products

A. Carbohydrate catabolism

1. Glycolysis (Figure 2-7)—a series of reactions that convert glucose to pyruvate or lactate. Also produce intermediate for other pathways of metabolism.

a. The process is located in the cytosol.
b. Under aerobic conditions, pyruvate, NADH, and ATP are produced.
c. Under anaerobic conditions, lactate and ATP are produced by utilizing NADH.
d. Important enzymes:

(1) Hexokinase (most cells)—irreversible reaction trapping glucose in cell.
(2) Glucokinase—found in liver; has high Km and Vmax.
(3) Phosphofructokinase—irreversible reaction forming fructose-1,6-bisphosphate. The rate-limiting step in the pathway.
(4) Pyruvate kinase—catalyzes the formation of ATP and production of pyruvate.

e. Regulators

(1) Hexokinase—inhibited by glucose 6-phosphate.
(2) Glucokinase—via glucokinase regulatory protein.

(a) Inhibited by fructose 6-phosphate.
(b) Stimulated by glucose.

(3) Phosphofructokinase—inhibited by ATP and citrate, stimulated by AMP and fructose-2, 6-bisphosphate.
(4) Pyruvate kinase—in muscle activated by fructose-1, 6-bisphosphate and inhibited by ATP. In the liver, inhibited by ATP and alanine.
(5) Lactic acidosis occurs when pyruvate metabolism is blocked.

f. Endocrine regulation of glycolysis

(1) Insulin stimulates.
(2) Glucagon inhibits.
(3) Epinephrine stimulates in muscle, inhibits in liver.

2. Pentose phosphate pathway

a. Source of pentoses for nucleotide synthesis.
b. Major source of NADPH for synthesis of fatty acids, cholesterol, steroids, and so forth.
c. Overall reaction (glucose-6-P + 2 NADP → ribulose—5 P +CO2 and 2 NADPH).
d. Transketolase and transaldolase catalyze reversible reactions in the pathway.

3. Tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) (Figure 2-8):

a. Metabolizes acetyl CoA to form ATP (12 molecules) and CO2.
b. Process located in mitochondria.
c. Consists of eight reactions that require the following five coenzymes:

(1) FAD
(2) Thiamine pyrophosphate
(3) Lipoic acid
(4) Coenzyme A
(5) NAD+

d. Provides substrates for biosynthetic processes.

(1) Citrate used for fatty acid synthesis.
(2) Succinyl CoA for heme synthesis.
(3) Oxaloacetate for glucose synthesis.
(4) Alpha ketoglutarate for nonessential amino acid synthesis.

e. Important irreversible regulatory enzymes

(1) Alpha ketoglutarate dehydrogenase—inhibited by NADH.
(2) Citrate synthase—inhibited by NADH.
(3) Isocitrate dehydrogenase—inhibited by ATP and stimulated by ADP. This also is the rate-limiting step in the cycle.

f. Overall reaction (each acetyl CoA = 12 ATP)

(1) Acetyl CoA + 3 NAD + FAD + GTP + Pi = 2 CO2 + 3 NADH + FADH2 + GTP.

4. Electron transport chain (Figure 2-9):

a. Located in the mitochondria where NADH and FADH2 are produced from oxidation reactions.
b. Composed of four protein complexes (all contain iron):

(1) NADH-CoQ reductase.
(2) Succinyl-CoQ reductase.
(3) Cytochrome c reductase.
(4) Cytochrome c oxidase (inhibited by cyanide, carbon monoxide, and azide).

5. Glycogenolysis—the breakdown of glycogen to form glucose.

a. Important enzymes

(1) Phosphorylase—phosphorylates the α 1, 4 bonds of glycogen, resulting in the release of glucose 1-phosphate.
(2) Debranching enzyme and α 1, 6 glucosidase—responsible for cleaving α 1, 6 bonds in a two-step process to release glucose-1-phosphate and free glucose.

b. Regulation

(1) Glucagons and epinephrine through cAMP activate protein kinases, which phosphorylate the phosphorylase enzyme, converting it to the active form of the enzyme.
(2) Insulin dephosphorylates the phosphorylase enzyme, inactivating it.
(3) Allosteric inhibitors of phosphorylase include ATP, creatine phosphate, and glucose-6-phosphate.
(4) Allosteric stimulators include AMP and glucose (in liver).

6. Glycogen storage disease refers to a number of diseases that result from defects in enzymes required for glycogen synthesis or glycogen degradation (Von Gierke disease results from deficiencies of glucose-6-phosphatase).

B. Lipid catabolism (Figure 2-10):

1. β oxidation—the process by which fatty acids are broken down to acetyl CoA and ultimately utilized as a source of energy in the TCA cycle.
2. The process is located in the mitochondria.
3. Fatty acids are delivered to the mitochondria from cytoplasm by the carnitine shuttle.

a. Two enzymes are involved in transporting large fatty acids into mitochondria:

(1) Carnitine acyltransferase-1—associates carnitine with the fatty acid to form acyl carnitine (releases CoA).
(2) Carnitine acyltransferase-2—reassociates the fatty acid with CoA. This enzyme is inhibited by malonyl CoA.

4. Important enzymes for β oxidation

a. Fatty acyl CoA dehydrogenases—specific for fatty acids of different chain lengths. Ultimately this produces a β ketoacyl CoA and NADH.
b. Thiolase—adds a CoA, which results in the release of acetyl CoA.

5. Regulators

a. Regulation of lipid catabolism is primarily through activation of hormone-sensitive lipase, which degrades triglycerides into fatty acids and glycerol. Free fatty acids readily enter the cell and become fatty acid acyl CoA by fatty acyl CoA synthetase.

(1) Glucagons, epinephrine, and ACTH stimulate lipase.
(2) Insulin inhibits lipase.

6. Ketone metabolism—under conditions of reduced intake of carbohydrate and increased β oxidation of fatty acids, ketone bodies are formed. Since most of the oxaloacetate is being utilized for gluconeogenesis, acetyl CoA resulting from β oxidation cannot be condensed and further metabolized in the TCA cycle. Acetyl CoA is then conserved by converting it to acetoacetate and β-hydroxybutyrate in the liver.

a. Ketone bodies may serve as a source of energy for extrahepatic tissues.

(1) Heart
(2) Skeletal muscle
(3) Kidney
(4) Brain

b. Accumulation of ketone bodies results in ketoacidosis.
c. Ketoacidosis is associated with excessive fatty acid oxidation associated with a lack of insulin.
d. Hyperlipidemia results from defects in lipoprotein metabolism.

(1) Type I results from the accumulation of triglycerides.
(2) Type II results from the accumulation of cholesterol.
(3) Type III results from the accumulation of both triglyceride and cholesterol.

C. Cholesterol catabolism (Figure 2-11):

1. Most cholesterol is eliminated from the body via the feces after conversion to bile salt in the liver.

a. Cholic acid and chenodeoxycholic acid are the major bile acids.
b. Bile salts are produced by the addition of an amino acid to the bile acid.

(1) Glycocholate (cholic acid and glycine).
(2) Glycochenodeoxycholic (chenodeoxycholic acid and glycine).
(3) Taurine may also be added to bile acids to produce comparable bile salts.

2. Enterohepatic circulation accounts for the resorption of most of the bile acids secreted from the liver.
D. Protein catabolism

1. Two major enzyme systems are responsible for protein degradation:

a. Ubiquitin-proteosome mechanism—proteins tagged with molecules of ubiquitin are recognized by the proteolytic molecule proteasome, which degrades the protein to amino acids.
b. Lysosomes—primarily responsible for digesting extracellular enzymes.

2. Pyridoxal phosphate (vitamin B6) is an important coenzyme in transamination reactions using a class of enzymes known as aminotransferases. This is important since the products of this reaction (α keto acids and glutamate) can be used as amino group donors for the synthesis of essential amino acids (glutamate) or enter metabolic pathways for energy metabolism (α keto acids).
3. The liver is the main site for amino acid catabolism where amino groups are removed, converted to urea, and excreted.
4. Every amino acid has a corresponding α keto acid that can be metabolized for energy.

a. α ketoglutarate (glutamate).
b. Oxaloacetate (aspartate).
c. Pyruvate (alanine).

5. The carbon groups are further metabolized to pyruvate, acetyl CoA, acetoacetyl CoA, α ketoglutarate, succinyl CoA, fumarate, or oxaloacetate.
6. Peripheral amino acids can be transported to the liver as part of alanine (alanine aminotransferase), glutamate (glutamate aminotransferase), or glutamine.
7. Phenylketonuria, caused by a deficiency of phenylalanine hydroxylase, results in the inability to metabolize phenylalanine. Aspartame, since it contains phenylalanine, is also contraindicated in individuals with this deficiency.
8. Maple syrup urine disease is caused by a deficiency in branched-chain α ketoacid dehydrogenase.
9. Albinism is caused by a defect in tyrosine metabolism and subsequent inability to produce melanin.
10. Since these enzymes are normally intracellular enzymes, elevated plasma levels of aminotransferases indicate damage to tissues containing cells rich in these enzymes (i.e., the liver).
11. Only the liver can make urea since it is the only tissue that has arginase. Four ATPs are needed for each cycle.
12. Urea cycle (Figure 2-12):

E. Nucleotide catabolism

1. Purine nucleotides—degraded to uric acid through a series of reactions catalyzed by the following enzymes:

a. Adenosine deaminase—removes the amino group.
b. 5′ nucleotidase—converts the nucleotide to nucleoside.
c. Purine nucleoside phosphorylase—releases the bases (guanine and hypoxanthine).
d. Guanine is deaminated and hypoxanthine oxidized to xanthine.
e. Xanthine is oxidized to uric acid.
f. Gout—caused by the overproduction or under-excretion of uric acid.

2. Pyrimidine nucleotides—pyrimidine ring is opened and degraded to β alanine and β aminoisobutyrate, which can be further metabolized in the citric acid cycle.

image

Figure 2-7 Coupling of the reactions of glycolysis with formation of lactic acid and ethanol in fermentations. Steps a through g describe the Embden-Meyerhof-Parnas pathway. Generation of 2 ATP in step b can provide all of the cell’s energy.

(From Metzler DE: Biochemistry, ed 2, Academic Press, San Diego, 2003.)

image

Figure 2-8 Reactions of the citric acid cycle (Krebs tricarboxylic acids cycle). Asterisks designate positions of isotropic label from entrance of carboxyl-labeled acetate into the cycle. Note that it is not the two-carbon atoms from acetyl CoA that are immediately removed as CO2, but two atoms from oxaloacetate. Only after several turns of the cycle are the carbon atoms of the acetyl CoA completely converted to CO2. Nevertheless, the cycle can properly be regarded as a mechanism of oxidation of acetyl groups to CO2. Daggers (†) designate the position of 2H introduced into malate as 2H+ from the medium. FAD§ designates covalently bound 8-histidyl-FAD. 2-oxyglutarate = α-ketoglutarate.

(From Metzler DE: Biochemistry, ed 2, Academic Press, San Diego, 2003.)

image

Figure 2-9 An abbreviated version of the electron transport chain of mitochondria. Four electrons reduce O2 to 2H2O.

(From Metzler DE: Biochemistry, ed 2, Academic Press, San Diego, 2003.)

image

Figure 2-10 An overall view of some metabolic sequences. Several major pathways of catabolism are indicated by heavy lines. The glycolysis pathway, leading to pyruvate and lactate, starts at the top left, while the β oxidation pathway of fatty acids is on the right. Biosynthetic routes are shown in thin, dark lines. A few of the points of synthesis and utilization of ATP are indicated by light lines. Some of the oxidation-reduction reactions that produce or utilize the reduced hydrogen carriers NADH, NADPH, and FADH2 are also indicated. The citric acid cycle, a major supplier of these molecules, is shown at the bottom right, while photosynthesis, the source of reduced hydrogen, carries in green plants, and the source of nearly all energy for life, is shown at the bottom left.

(From Metzler DE: Biochemistry, ed 2, Academic Press, San Diego, 2003.)

image

Figure 2-11 Movement of triacylglycerols from liver and intestine to body cells and lipid carriers of blood. VLDL, very-low-density lipoprotein that contains triacylglycerols, phospholipids, cholesterol, and apolipoproteins B and C; IDL, intermediate-density lipoproteins found in human plasma; LDL, low-density lipoproteins that have lost most of their triacylglycerols.

(From Metzler DE: Biochemistry, ed 2, Academic Press, San Diego, 2003.)

image

Figure 2-12 Integration of the urea cycle with mitochondrial metabolism. Thinner lines trace the flow of nitrogen into urea upon deamination of amino acids or upon removal of nitrogen from the side chain of glutamine.

(From Metzler DE: Biochemistry, ed 2, Academic Press, San Diego, 2003.)

2.4 Anabolism

The process by which small simple compounds are used to synthesize more complex molecules, including carbohydrates, lipi/>

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Jan 5, 2015 | Posted by in General Dentistry | Comments Off on 2: Biochemistry and Physiology

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