CHAPTER 1 General Principles & Energy Production in Medical Physiology 15transcript of a small segment of the DNA chain. For comparison,the molecules of tRNA contain only 70–80 nitrogenous bases,compared with hundreds in mRNA and 3 billion in DNA.AMINO ACIDS & PROTEINSAMINO ACIDSAmino acids that form the basic building blocks for proteinsare identified in Table 1–3. These amino acids are often re-ferred to by their corresponding three-letter, or single-letterabbreviations. Various other important amino acids such asornithine, 5-hydroxytryptophan, L-dopa, taurine, and thy-roxine (T4) occur in the body but are not found in proteins.In higher animals, the L isomers of the amino acids are theonly naturally occurring forms in proteins. The L isomers ofhormones such as thyroxine are much more active than theD isomers. The amino acids are acidic, neutral, or basic in re-action, depending on the relative proportions of free acidic(–COOH) or basic (–NH2) groups in the molecule. Some ofthe amino acids are nutritionally essential amino acids, thatis, they must be obtained in the diet, because they cannot bemade in the body. Arginine and histidine must be providedthrough diet during times of rapid growth or recovery fromillness and are termed conditionally essential. All others arenonessential amino acids in the sense that they can be syn-thesized in vivo in amounts sufficient to meet metabolicneeds.FIGURE 1–14 Transcription of a typical mRNA. Steps in trans-cription from a typical gene to a processed mRNA are shown. Cap, cap site. (Modified from Baxter JD: Principles of endocrinology. In: Cecil Textbook of Medicine, 16th ed. Wyngaarden JB, Smith LH Jr (editors). Saunders, 1982.)Poly(A)Poly(A)Poly(A)GenemRNAPre-mRNARNAprocessingFlanking DNA Introns ExonsCapTranscriptionFlankingDNATranslationFIGURE 1–15 Diagrammatic outline of transcription to translation. From the DNA molecule, a messenger RNA is produced and presented to the ribosome. It is at the ribosome where charged tRNA match up with their complementary codons of mRNA to position the amino acid for growth of the polypeptide chain. DNA and RNA are represented as lines with multiple short projections representing the individual bases. Small boxes labeled A represent individual amino acids.PosttranscriptionalmodificationPosttranslationalmodificationTranslationDNAChain separationAmino acidtRNAadenylatetRNA-amino acid-adenylatecomplexA3 A2 A1Peptide chainMessenger RNACoding triplets forA3A4A2A4A1RibosomeActivatingenzymeRNA strand formedon DNA strand(transcription)
16 SECTION I Cellular & Molecular Basis of Medical PhysiologyTHE AMINO ACID POOLAlthough small amounts of proteins are absorbed from thegastrointestinal tract and some peptides are also absorbed,most ingested proteins are digested and their constituent ami-no acids absorbed. The body’s own proteins are being contin-uously hydrolyzed to amino acids and resynthesized. Theturnover rate of endogenous proteins averages 80–100 g/d, be-ing highest in the intestinal mucosa and practically nil in theextracellular structural protein, collagen. The amino acidsformed by endogenous protein breakdown are identical tothose derived from ingested protein. Together they form acommon amino acid pool that supplies the needs of the body(Figure 1–16).PROTEINSProteins are made up of large numbers of amino acids linkedinto chains by peptide bonds joining the amino group of oneamino acid to the carboxyl group of the next (Figure 1–17). Inaddition, some proteins contain carbohydrates (glycopro-teins) and lipids (lipoproteins). Smaller chains of amino acidsare called peptides or polypeptides. The boundaries betweenpeptides, polypeptides, and proteins are not well defined. Forthis text, amino acid chains containing 2–10 amino acid resi-dues are called peptides, chains containing more than 10 butfewer than 100 amino acid residues are called polypeptides,and chains containing 100 or more amino acid residues arecalled proteins.TABLE 1–3 Amino acids found in proteins.* Amino acids with aliphatic side chains Amino acids with acidic side chains, or their amidesAlanine (Ala, A) Aspartic acid (Asp, D)Valine (Val, V) Asparagine (Asn, N)Leucine (Leu, L) Glutamine (Gln, Q)Isoleucine (IIe, I) Glutamic acid (Glu, E)Hydroxyl-substituted amino acids γ-Carboxyglutamic acidb (Gla)Serine (Ser, S) Amino acids with side chains containing basic groupsThreonine (Thr, T) Argininec (Arg, R)Sulfur-containing amino acids Lysine (Lys, K)Cysteine (Cys, C) Hydroxylysineb (Hyl)Methionine (Met, M) Histidinec (His, H)SelenocysteineaImino acids (contain imino group but no amino group)Amino acids with aromatic ring side chains Proline (Pro, P)Phenylalanine (Phe, F) 4-Hydroxyprolineb (Hyp)Tyrosine (Tyr, Y) 3-HydroxyprolinebTryptophan (Trp, W)Those in bold type are the nutritionally essential amino acids. The generally accepted three-letter and one-letter abbreviations for the amino acids are shown in parentheses.aSelenocysteine is a rare amino acid in which the sulfur of cysteine is replaced by selenium. The codon UGA is usually a stop codon, but in certain situations it codes for selenocysteine.bThere are no tRNAs for these four amino acids; they are formed by post-translational modification of the corresponding unmodified amino acid in peptide linkage. There are tRNAs for selenocysteine and the remaining 20 amino acids, and they are incorporated into peptides and proteins under direct genetic control.cArginine and histidine are sometimes called “conditionally essential”—they are not necessary for maintenance of nitrogen balance, but are needed for normal growth.FIGURE 1–16 Amino acids in the body. There is an extensive network of amino acid turnover in the body. Boxes represent large pools of amino acids and some of the common interchanges are rep-resented by arrows. Note that most amino acids come from the diet and end up in protein, however, a large portion of amino acids are in-terconverted and can feed into and out of a common metabolic pool through amination reactions.Inert protein(hair, etc)Amino acidpoolBodyproteinDietUreaNH4+CommonmetabolicpoolTransaminationAminationDeaminationPurines,pyrimidinesHormones,neurotransmittersCreatineUrinaryexcretion
CHAPTER 1 General Principles & Energy Production in Medical Physiology 17The order of the amino acids in the peptide chains is calledthe primary structure of a protein. The chains are twisted andfolded in complex ways, and the term secondary structure ofa protein refers to the spatial arrangement produced by thetwisting and folding. A common secondary structure is a regu-lar coil with 3.7 amino acid residues per turn (α-helix).Another common secondary structure is a β-sheet. An anti-parallel β-sheet is formed when extended polypeptide chainsfold back and forth on one another and hydrogen bondingoccurs between the peptide bonds on neighboring chains. Par-allel β-sheets between polypeptide chains also occur. The ter-tiary structure of a protein is the arrangement of the twistedchains into layers, crystals, or fibers. Many protein moleculesare made of several proteins, or subunits (eg, hemoglobin),and the term quaternary structure is used to refer to thearrangement of the subunits into a functional structure.PROTEIN SYNTHESISThe process of protein synthesis, translation, is the conversionof information encoded in mRNA to a protein (Figure 1–15).As described previously, when a definitive mRNA reaches a ri-bosome in the cytoplasm, it dictates the formation of a polypep-tide chain. Amino acids in the cytoplasm are activated bycombination with an enzyme and adenosine monophosphate(adenylate), and each activated amino acid then combines witha specific molecule of tRNA. There is at least one tRNA for eachof the 20 unmodified amino acids found in large quantities inthe body proteins of animals, but some amino acids have morethan one tRNA. The tRNA–amino acid–adenylate complex isnext attached to the mRNA template, a process that occurs inthe ribosomes. The tRNA “recognizes” the proper spot to attachon the mRNA template because it has on its active end a set ofthree bases that are complementary to a set of three bases in aparticular spot on the mRNA chain. The genetic code is madeup of such triplets (codons), sequences of three purine, pyrimi-dine, or purine and pyrimidine bases; each codon stands for aparticular amino acid.Translation typically starts in the ribosomes with an AUG(transcribed from ATG in the gene), which codes for methio-nine. The amino terminal amino acid is then added, and thechain is lengthened one amino acid at a time. The mRNAattaches to the 40S subunit of the ribosome during proteinsynthesis, the polypeptide chain being formed attaches to the60S subunit, and the tRNA attaches to both. As the aminoacids are added in the order dictated by the codon, the ribo-some moves along the mRNA molecule like a bead on astring. Translation stops at one of three stop, or nonsense,codons (UGA, UAA, or UAG), and the polypeptide chain isreleased. The tRNA molecules are used again. The mRNAmolecules are typically reused approximately 10 times beforebeing replaced. It is common to have more than one ribosomeon a given mRNA chain at a time. The mRNA chain plus itscollection of ribosomes is visible under the electron micro-scope as an aggregation of ribosomes called a polyribosome.POSTTRANSLATIONAL MODIFICATIONAfter the polypeptide chain is formed, it “folds” into its biolog-ical form and can be further modified to the final protein byone or more of a combination of reactions that include hy-droxylation, carboxylation, glycosylation, or phosphorylationof amino acid residues; cleavage of peptide bonds that con-verts a larger polypeptide to a smaller form; and the furtherfolding, packaging, or folding and packaging of the proteininto its ultimate, often complex configuration. Protein foldingis a complex process that is dictated primarily by the sequenceof the amino acids in the polypeptide chain. In some instances,however, nascent proteins associate with other proteins calledchaperones, which prevent inappropriate contacts with otherproteins and ensure that the final “proper” conformation ofthe nascent protein is reached.Proteins also contain information that helps to direct themto individual cell compartments. Many proteins that are goingto be secreted or stored in organelles and most transmembraneproteins have at their amino terminal a signal peptide (leadersequence) that guides them into the endoplasmic reticulum.The sequence is made up of 15 to 30 predominantly hydropho-bic amino acid residues. The signal peptide, once synthesized,binds to a signal recognition particle (SRP), a complex mole-cule made up of six polypeptides and 7S RNA, one of the smallRNAs. The SRP stops translation until it binds to a translocon,a pore in the endoplasmic reticulum that is a heterotrimericstructure made up of Sec 61 proteins. The ribosome also binds,and the signal peptide leads the growing peptide chain into thecavity of the endoplasmic reticulum (Figure 1–18). The signalFIGURE 1–17 Amino acid structure and formation of peptide bonds. The dashed line shows where peptide bonds are formed be-tween two amino acids. The highlighted area is released as H2O. R, remainder of the amino acid. For example, in glycine, R = H; in glutamate, R = —(CH2)2—COO–.HHHC OH H–NRORCHCHNOCHCRONCHAmino acid Polypeptide chain
18 SECTION I Cellular & Molecular Basis of Medical Physiologypeptide is next cleaved from the rest of the peptide by a signalpeptidase while the rest of the peptide chain is still being syn-thesized. SRPs are not the only signals that help to direct pro-teins to their proper place in or out of the cell; other signalsequences, posttranslational modifications, or both (eg, glyco-sylation) can serve this function.PROTEIN DEGRADATIONLike protein synthesis, protein degradation is a carefully regu-lated, complex process. It has been estimated that overall, up to30% of newly produced proteins are abnormal, such as can oc-cur during improper folding. Aged normal proteins also need tobe removed as they are replaced. Conjugation of proteins to the74-amino-acid polypeptide ubiquitin marks them for degrada-tion. This polypeptide is highly conserved and is present in spe-cies ranging from bacteria to humans. The process of bindingubiquitin is called ubiquitination, and in some instances, mul-tiple ubiquitin molecules bind (polyubiquitination). Ubiquiti-nation of cytoplasmic proteins, including integral proteins ofthe endoplasmic reticulum, marks the proteins for degradationin multisubunit proteolytic particles, or proteasomes. Ubiquit-ination of membrane proteins, such as the growth hormone re-ceptors, also marks them for degradation, however these can bedegraded in lysosomes as well as via the proteasomes.There is an obvious balance between the rate of productionof a protein and its destruction, so ubiquitin conjugation is ofmajor importance in cellular physiology. The rates at whichindividual proteins are metabolized vary, and the body hasmechanisms by which abnormal proteins are recognized anddegraded more rapidly than normal body constituents. Forexample, abnormal hemoglobins are metabolized rapidly inindividuals with congenital hemoglobinopathies.CATABOLISM OF AMINO ACIDSThe short-chain fragments produced by amino acid, carbohy-drate, and fat catabolism are very similar (see below). Fromthis common metabolic pool of intermediates, carbohy-drates, proteins, and fats can be synthesized. These fragmentscan enter the citric acid cycle, a final common pathway of ca-tabolism, in which they are broken down to hydrogen atomsand CO2. Interconversion of amino acids involve transfer, re-moval, or formation of amino groups. Transamination reac-tions, conversion of one amino acid to the corresponding ketoacid with simultaneous conversion of another keto acid to anamino acid, occur in many tissues:Alanine + α-Ketoglutarate →← Pyruvate + GlutamateThe transaminases involved are also present in the circula-tion. When damage to many active cells occurs as a result of apathologic process, serum transaminase levels rise. An exam-ple is the rise in plasma aspartate aminotransferase (AST)following myocardial infarction.Oxidative deamination of amino acids occurs in the liver.An imino acid is formed by dehydrogenation, and this com-pound is hydrolyzed to the corresponding keto acid, with pro-duction of NH4+:Amino acid + NAD+ → Imino acid + NADH + H+Imino acid + H2O → Keto acid + NH4+Interconversions between the amino acid pool and thecommon metabolic pool are summarized in Figure 1–19.Leucine, isoleucine, phenylalanine, and tyrosine are said to beketogenic because they are converted to the ketone body ace-toacetate (see below). Alanine and many other amino acidsare glucogenic or gluconeogenic; that is, they give rise tocompounds that can readily be converted to glucose.UREA FORMATIONMost of the NH4+ formed by deamination of amino acids in theliver is converted to urea, and the urea is excreted in the urine.The NH4+ forms carbamoyl phosphate, and in the mitochon-dria it is transferred to ornithine, forming citrulline. The en-zyme involved is ornithine carbamoyltransferase. Citrulline isconverted to arginine, after which urea is split off and ornithineis regenerated (urea cycle; Figure 1–20). The overall reaction inthe urea cycle consumes 3 ATP (not shown) and thus requiressignificant energy. Most of the urea is formed in the liver, and insevere liver disease the blood urea nitrogen (BUN) falls andblood NH3 rises (see Chapter 29). Congenital deficiency of or-nithine carbamoyltransferase can also lead to NH3 intoxication,even in individuals who are heterozygous for this deficiency.FIGURE 1–18 Translation of protein into endoplasmic reticulum according to the signal hypothesis. The ribosomes syn-thesizing a protein move along the mRNA from the 5′ to the 3′ end. When the signal peptide of a protein destined for secretion, the cell membrane, or lysosomes emerges from the large unit of the ribosome, it binds to a signal recognition particle (SRP), and this arrests further translation until it binds to the translocon on the endoplasmic reticu-lum. N, amino end of protein; C, carboxyl end of protein. (Reproduced, with permission, from Perara E, Lingappa VR: Transport of proteins into and across the endoplasmic reticulum membrane. In: Protein Transfer and Organelle Biogenesis. Das RC, Robbins PW (editors). Academic Press, 1988.)5′3′NNNNNNNNCCCCUAASRP
CHAPTER 1 General Principles & Energy Production in Medical Physiology 19METABOLIC FUNCTIONS OF AMINO ACIDSIn addition to providing the basic building blocks for proteins,amino acids also have metabolic functions. Thyroid hor-mones, catecholamines, histamine, serotonin, melatonin, andintermediates in the urea cycle are formed from specific ami-no acids. Methionine and cysteine provide the sulfur con-tained in proteins, CoA, taurine, and other biologicallyimportant compounds. Methionine is converted into S-ade-nosylmethionine, which is the active methylating agent in thesynthesis of compounds such as epinephrine.CARBOHYDRATESCarbohydrates are organic molecules made of equal amountsof carbon and H2O. The simple sugars, or monosaccharides,including pentoses (5 carbons; eg, ribose) and hexoses (6 car-bons; eg, glucose) perform both structural (eg, as part of nu-cleotides discussed previously) and functional roles (eg,inositol 1,4,5 trisphosphate acts as a cellular signaling mole-cules) in the body. Monosaccharides can be linked together toform disaccharides (eg, sucrose), or polysaccharides (eg, gly-cogen). The placement of sugar moieties onto proteins (glyco-proteins) aids in cellular targeting, and in the case of someFIGURE 1–19 Involvement of the citric acid cycle in transamination and gluconeogenesis. The bold arrows indicate the main pathway of gluconeogenesis. Note the many entry positions for groups of amino acids into the citric acid cycle. (Reproduced with permission from Murray RK et al: Harper’s Biochemistry, 26th ed. McGraw-Hill, 2003.)TransaminaseTransaminaseTransaminasePhosphoenolpyruvatecarboxykinaseOxaloacetateAspartateCitrateα-KetoglutarateSuccinyl-CoAFumaratePhosphoenolpyruvateCO2CO2PyruvateAlanineAcetyl-CoAGlutamateHistidineProlineGlutamineArginineIsoleucineMethionineValineHydroxyprolineSerineCysteineThreonineGlycineTyrosinePhenylalaninePropionateGlucoseTryptophanLactateFIGURE 1–20 Urea cycle. The processing of NH3 to urea for ex-cretion contains several coordinative steps in both the cytoplasm (Cy-to) and the mitochondria (Mito). The production of carbamoyl phosphate and its conversion to citrulline occurs in the mitochondria, whereas other processes are in the cytoplasm.NH2+NH3+NH3+NH4+NH3H3N+ArgininosuccinateH2NCHNCOO−COO−HC(CH2)3(CH2)3HC——ONH3+H2NCPiHNCOO−HC(CH2)3——FumarateAspartateCitrulline + NO ArginineCarbamoylphosphateUreaOrnithineO NH2 C NH2——CytoMito
20 SECTION I Cellular & Molecular Basis of Medical Physiologyreceptors, recognition of signaling molecules. In this sectionwe will discuss a major role for carbohydrates in physiology,the production and storage of energy.Dietary carbohydrates are for the most part polymers ofhexoses, of which the most important are glucose, galactose,and fructose (Figure 1–21). Most of the monosaccharidesoccurring in the body are the D isomers. The principal prod-uct of carbohydrate digestion and the principal circulatingsugar is glucose. The normal fasting level of plasma glucose inperipheral venous blood is 70 to 110 mg/dL (3.9–6.1 mmol/L). In arterial blood, the plasma glucose level is 15 to 30 mg/dL higher than in venous blood.Once it enters the cells, glucose is normally phosphorylatedto form glucose 6-phosphate. The enzyme that catalyzes thisreaction is hexokinase. In the liver, there is an additionalenzyme called glucokinase, which has greater specificity forglucose and which, unlike hexokinase, is increased by insulinand decreased in starvation and diabetes. The glucose 6-phos-phate is either polymerized into glycogen or catabolized. Theprocess of glycogen formation is called glycogenesis, and gly-cogen breakdown is called glycogenolysis. Glycogen, the stor-age form of glucose, is present in most body tissues, but themajor supplies are in the liver and skeletal muscle. The break-down of glucose to pyruvate or lactate (or both) is called gly-colysis. Glucose catabolism proceeds via cleavage throughfructose to trioses or via oxidation and decarboxylation topentoses. The pathway to pyruvate through the trioses is theEmbden–Meyerhof pathway, and that through 6-phospho-gluconate and the pentoses is the direct oxidative pathway(hexose monophosphate shunt). Pyruvate is converted toacetyl-CoA. Interconversions between carbohydrate, fat, andprotein include conversion of the glycerol from fats to dihy-droxyacetone phosphate and conversion of a number of aminoacids with carbon skeletons resembling intermediates in theEmbden–Meyerhof pathway and citric acid cycle to these inter-mediates by deamination. In this way, and by conversion of lac-tate to glucose, nonglucose molecules can be converted toglucose (gluconeogenesis). Glucose can be converted to fatsthrough acetyl-CoA, but because the conversion of pyruvate toacetyl-CoA, unlike most reactions in glycolysis, is irreversible,fats are not converted to glucose via this pathway. There istherefore very little net conversion of fats to carbohydrates inthe body because, except for the quantitatively unimportantproduction from glycerol, there is no pathway for conversion.CITRIC ACID CYCLEThe citric acid cycle (Krebs cycle, tricarboxylic acid cycle) is asequence of reactions in which acetyl-CoA is metabolized toCO2 and H atoms. Acetyl-CoA is first condensed with theanion of a four-carbon acid, oxaloacetate, to form citrate andHS-CoA. In a series of seven subsequent reactions, 2CO2 mol-ecules are split off, regenerating oxaloacetate (Figure 1–22).Four pairs of H atoms are transferred to the flavoprotein–cytochrome chain, producing 12ATP and 4H2O, of which2H2O is used in the cycle. The citric acid cycle is the commonpathway for oxidation to CO2 and H2O of carbohydrate, fat,and some amino acids. The major entry into it is through acetyl-CoA, but a number of amino acids can be converted to citricacid cycle intermediates by deamination. The citric acid cyclerequires O2 and does not function under anaerobic conditions.ENERGY PRODUCTIONThe net production of energy-rich phosphate compoundsduring the metabolism of glucose and glycogen to pyruvatedepends on whether metabolism occurs via the Embden–Meyerhof pathway or the hexose monophosphate shunt. Byoxidation at the substrate level, the conversion of 1 mol ofphosphoglyceraldehyde to phosphoglycerate generates 1 molof ATP, and the conversion of 1 mol of phosphoenolpyruvateto pyruvate generates another. Because 1 mol of glucose 6-phosphate produces, via the Embden–Meyerhof pathway, 2mol of phosphoglyceraldehyde, 4 mol of ATP is generated permole of glucose metabolized to pyruvate. All these reactionsoccur in the absence of O2 and consequently represent anaer-obic production of energy. However, 1 mol of ATP is used informing fructose 1,6-diphosphate from fructose 6-phosphateand 1 mol in phosphorylating glucose when it enters the cell.Consequently, when pyruvate is formed anaerobically fromglycogen, there is a net production of 3 mol of ATP per moleof glucose 6-phosphate; however, when pyruvate is formedfrom 1 mol of blood glucose, the net gain is only 2 mol of ATP.A supply of NAD+ is necessary for the conversion of phos-phoglyceraldehyde to phosphoglycerate. Under anaerobicconditions (anaerobic glycolysis), a block of glycolysis at thephosphoglyceraldehyde conversion step might be expected todevelop as soon as the available NAD+ is converted to NADH.However, pyruvate can accept hydrogen from NADH, form-ing NAD+ and lactate😛yruvate + NADH →← Lactate + NAD+In this way, glucose metabolism and energy production cancontinue for a while without O2. The lactate that accumulatesis converted back to pyruvate when the O2 supply is restored,with NADH transferring its hydrogen to the flavoprotein–cytochrome chain.FIGURE 1–21 Structures of principal dietary hexoses. Glu-cose, galactose, and fructose are shown in their naturally occurring D isomers.————COHCHHOCOHHCOHHCOHHCH2OHCO——COHCHHOCOHHCHHOCOHHCH2OHCHHOCOHHCOHHCH2OHCH2OHD-Glucose D-Galactose D-Fructose
CHAPTER 1 General Principles & Energy Production in Medical Physiology 21During aerobic glycolysis, the net production of ATP is 19times greater than the two ATPs formed under anaerobic con-ditions. Six ATPs are formed by oxidation via the flavopro-tein–cytochrome chain of the two NADHs produced when 2mol of phosphoglyceraldehyde is converted to phosphoglyc-erate (Figure 1–22), six ATPs are formed from the twoNADHs produced when 2 mol of pyruvate is converted toacetyl-CoA, and 24 ATPs are formed during the subsequenttwo turns of the citric acid cycle. Of these, 18 are formed byoxidation of six NADHs, 4 by oxidation of two FADH2s, and 2by oxidation at the substrate level when succinyl-CoA is con-verted to succinate. This reaction actually produces GTP, butthe GTP is converted to ATP. Thus, the net production of ATPper mol of blood glucose metabolized aerobically via theEmbden–Meyerhof pathway and citric acid cycle is 2 + [2 × 3]+ [2 × 3] + [2 × 12] = 38.Glucose oxidation via the hexose monophosphate shuntgenerates large amounts of NADPH. A supply of this reducedcoenzyme is essential for many metabolic processes. Thepentoses formed in the process are building blocks fornucleotides (see below). The amount of ATP generateddepends on the amount of NADPH converted to NADH andthen oxidized.“DIRECTIONAL-FLOW VALVES”Metabolism is regulated by a variety of hormones and other fac-tors. To bring about any net change in a particular metabolicprocess, regulatory factors obviously must drive a chemical re-action in one direction. Most of the reactions in intermediarymetabolism are freely reversible, but there are a number of “di-rectional-flow valves,” ie, reactions that proceed in one direc-tion under the influence of one enzyme or transport mechanismand in the opposite direction under the influence of another.Five examples in the intermediary metabolism of carbohydrateare shown in Figure 1–23. The different pathways for fatty acidsynthesis and catabolism (see below) are another example. Reg-ulatory factors exert their influence on metabolism by acting di-rectly or indirectly at these directional-flow valves.GLYCOGEN SYNTHESIS & BREAKDOWNGlycogen is a branched glucose polymer with two types of gly-coside linkages: 1:4α and 1:6α (Figure 1–24). It is synthesizedon glycogenin, a protein primer, from glucose 1-phosphatevia uridine diphosphoglucose (UDPG). The enzyme glycogensynthase catalyses the final synthetic step. The availability ofFIGURE 1–22 Citric acid cycle. The numbers (6C, 5C, etc) indicate the number of carbon atoms in each of the intermediates. The conversion of pyruvate to acetyl-CoA and each turn of the cycle provide four NADH and one FADH2 for oxidation via the flavoprotein-cytochrome chain plus formation of one GTP that is readily converted to ATP.PPyruvate 3CAcetyl-CoA 2COxaloacetate 4CMalate 4CFumarate 4CSuccinate 4CSuccinyl-CoA 4CCitrate 6CIsocitrate 6Cα-Ketoglutarate 5CNAD+NAD+NADH + H+NADH + H+FADGTPGDPFADH2CO2CO2CO2NAD+NADH + H+NAD+NADH + H+
22 SECTION I Cellular & Molecular Basis of Medical Physiologyglycogenin is one of the factors determining the amount ofglycogen synthesized. The breakdown of glycogen in 1:4αlinkage is catalyzed by phosphorylase, whereas another en-zyme catalyzes the breakdown of glycogen in 1:6α linkage.FACTORS DETERMINING THE PLASMA GLUCOSE LEVELThe plasma glucose level at any given time is determined bythe balance between the amount of glucose entering thebloodstream and the amount leaving it. The principal deter-minants are therefore the dietary intake; the rate of entry intothe cells of muscle, adipose tissue, and other organs; and theglucostatic activity of the liver (Figure 1–25). Five percent ofingested glucose is promptly converted into glycogen in theliver, and 30–40% is converted into fat. The remainder is me-tabolized in muscle and other tissues. During fasting, liver gly-cogen is broken down and the liver adds glucose to thebloodstream. With more prolonged fasting, glycogen is de-pleted and there is increased gluconeogenesis from amino ac-ids and glycerol in the liver. Plasma glucose declines modestlyto about 60 mg/dL during prolonged starvation in normal in-dividuals, but symptoms of hypoglycemia do not occur be-cause gluconeogenesis prevents any further fall.FIGURE 1–23 Directional flow valves in energy production reactions. In carbohydrate metabolism there are several reactions that proceed in one direction by one mechanism and in the other direction by a different mechanism, termed “directional-flow valves.” Five examples of these reactions are illustrated (numbered at left). The double line in ex-ample 5 represents the mitochondrial membrane. Pyruvate is converted to malate in mitochondria, and the malate diffuses out of the mitochon-dria to the cytosol, where it is converted to phosphoenolpyruvate.PyruvatePyruvateOxaloacetateMalateMalateOxaloacetate5. Phosphoenolpyruvate4. Fructose 6-phosphatePhosphoenolpyruvatecarboxykinaseFructose 1,6-biphosphateFructose 1,6-biphosphatasePhospho-fructokinase3. Glucose 1-phosphateGlycogenPhosphorylaseGlycogen synthase2. Glucose1. Glucose entry into cells and glucose exit from cellsGlucose 6-phosphateGlucose 6-phosphataseHexokinasePyruvate kinaseADP ATPFIGURE 1–24 Glycogen formation and breakdown. Glycogen is the main storage for glucose in the cell. It is cycled: built up from glucose 6-phosphate when energy is stored and broken down to glucose 6-phosphate when energy is required. Note the intermediate glucose 1-phosphate and enzymatic control by phosphorylase a and glycogen kinase.CH2OHOCH2OHOOCH2OHOOOCH2OHOCH2OOOCH2OHOCH2OHOOCH2OCH2OHOCH2OHOOO1:6α linkage1:4α linkagePOO−O−POO−O−Glucose1-phosphateGlucose6-phosphateUridinediphospho-glucoseGlycogenPhosphorylase aGlycogensynthase
CHAPTER 1 General Principles & Energy Production in Medical Physiology 23METABOLISM OF HEXOSES OTHER THAN GLUCOSEOther hexoses that are absorbed from the intestine include ga-lactose, which is liberated by the digestion of lactose and con-verted to glucose in the body; and fructose, part of which isingested and part produced by hydrolysis of sucrose. Afterphosphorylation, galactose reacts with uridine diphosphoglu-cose (UDPG) to form uridine diphosphogalactose. The uri-dine diphosphogalactose is converted back to UDPG, andthe UDPG functions in glycogen synthesis. This reaction isreversible, and conversion of UDPG to uridine diphospho-galactose provides the galactose necessary for formation ofglycolipids and mucoproteins when dietary galactose intake isinadequate. The utilization of galactose, like that of glucose,depends on insulin. In the inborn error of metabolism knownas galactosemia, there is a congenital deficiency of galactose1-phosphate uridyl transferase, the enzyme responsible for thereaction between galactose 1-phosphate and UDPG, so thatingested galactose accumulates in the circulation. Serious dis-turbances of growth and development result. Treatment withgalactose-free diets improves this condition without leading togalactose deficiency, because the enzyme necessary for the for-mation of uridine diphosphogalactose from UDPG is present.Fructose is converted in part to fructose 6-phosphate andthen metabolized via fructose 1,6-diphosphate. The enzymecatalyzing the formation of fructose 6-phosphate is hexoki-nase, the same enzyme that catalyzes the conversion of glu-cose to glucose 6-phosphate. However, much more fructoseis converted to fructose 1-phosphate in a reaction catalyzedby fructokinase. Most of the fructose 1-phosphate is thensplit into dihydroxyacetone phosphate and glyceraldehyde.The glyceraldehyde is phosphorylated, and it and the dihy-droxyacetone phosphate enter the pathways for glucosemetabolism. Because the reactions proceeding through phos-phorylation of fructose in the 1 position can occur at a nor-mal rate in the absence of insulin, it has been recommendedthat fructose be given to diabetics to replenish their carbohy-drate stores. However, most of the fructose is metabolized inthe intestines and liver, so its value in replenishing carbohy-drate elsewhere in the body is limited.Fructose 6-phosphate can also be phosphorylated in the 2position, forming fructose 2,6-diphosphate. This compoundis an important regulator of hepatic gluconeogenesis. Whenthe fructose 2,6-diphosphate level is high, conversion of fruc-tose 6-phosphate to fructose 1,6-diphosphate is facilitated,and thus breakdown of glucose to pyruvate is increased. Adecreased level of fructose 2,6-diphosphate facilitates thereverse reaction and consequently aids gluconeogenesis.FATTY ACIDS & LIPIDSThe biologically important lipids are the fatty acids and their de-rivatives, the neutral fats (triglycerides), the phospholipids andrelated compounds, and the sterols. The triglycerides are madeup of three fatty acids bound to glycerol (Table 1–4). Naturallyoccurring fatty acids contain an even number of carbon atoms.They may be saturated (no double bonds) or unsaturated (de-hydrogenated, with various numbers of double bonds). Thephospholipids are constituents of cell membranes and providestructural components of the cell membrane, as well as an im-portant source of intra- and intercellular signaling molecules.Fatty acids also are an important source of energy in the body.FATTY ACID OXIDATION & SYNTHESISIn the body, fatty acids are broken down to acetyl-CoA, whichenters the citric acid cycle. The main breakdown occurs in themitochondria by β-oxidation. Fatty acid oxidation begins withactivation (formation of the CoA derivative) of the fatty acid,a reaction that occurs both inside and outside the mitochon-dria. Medium- and short-chain fatty acids can enter the mito-chondria without difficulty, but long-chain fatty acids must bebound to carnitine in ester linkage before they can cross theinner mitochondrial membrane. Carnitine is β-hydroxy-γ-tri-methylammonium butyrate, and it is synthesized in the bodyfrom lysine and methionine. A translocase moves the fattyacid–carnitine ester into the matrix space. The ester is hydro-lyzed, and the carnitine recycles. β-oxidation proceeds by se-rial removal of two carbon fragments from the fatty acid(Figure 1–26). The energy yield of this process is large. For ex-ample, catabolism of 1 mol of a six-carbon fatty acid throughthe citric acid cycle to CO2 and H2O generates 44 mol of ATP,compared with the 38 mol generated by catabolism of 1 mol ofthe six-carbon carbohydrate glucose.KETONE BODIESIn many tissues, acetyl-CoA units condense to form acetoacetyl-CoA (Figure 1–27). In the liver, which (unlike other tissues)contains a deacylase, free acetoacetate is formed. This β-ketoacid is converted to β-hydroxybutyrate and acetone, andbecause these compounds are metabolized with difficulty inFIGURE 1–25 Plasma glucose homeostasis. Notice the gluco-static function of the liver, as well as the loss of glucose in the urine when the renal threshold is exceeded (dashed arrows).Kidney Brain FatMuscle andother tissuesLiverAminoacidsGlycerolDietIntestinePlasma glucose70 mg/dL(3.9 mmol/L)Urine (when plasma glucose> 180 mg/dL)Lactate
24 SECTION I Cellular & Molecular Basis of Medical Physiologythe liver, they diffuse into the circulation. Acetoacetate is alsoformed in the liver via the formation of 3-hydroxy-3-methyl-glutaryl-CoA, and this pathway is quantitatively more impor-tant than deacylation. Acetoacetate, β-hydroxybutyrate, andacetone are called ketone bodies. Tissues other than livertransfer CoA from succinyl-CoA to acetoacetate and metabo-lize the “active” acetoacetate to CO2 and H2O via the citricacid cycle. Ketone bodies are also metabolized via other path-ways. Acetone is discharged in the urine and expired air. Animbalance of ketone bodies can lead to serious health prob-lems (Clinical Box 1–3).CELLULAR LIPIDSThe lipids in cells are of two main types: structural lipids,which are an inherent part of the membranes and other partsof cells; and neutral fat, stored in the adipose cells of the fatdepots. Neutral fat is mobilized during starvation, but struc-tural lipid is preserved. The fat depots obviously vary in size,but in nonobese individuals they make up about 15% of bodyweight in men and 21% in women. They are not the inertstructures they were once thought to be but, rather, active dy-namic tissues undergoing continuous breakdown and resyn-thesis. In the depots, glucose is metabolized to fatty acids, andneutral fats are synthesized. Neutral fat is also broken down,and free fatty acids are released into the circulation.A third, special type of lipid is brown fat, which makes up asmall percentage of total body fat. Brown fat, which is some-what more abundant in infants but is present in adults as well,is located between the scapulas, at the nape of the neck, alongthe great vessels in the thorax and abdomen, and in otherscattered locations in the body. In brown fat depots, the fatcells as well as the blood vessels have an extensive sympatheticinnervation. This is in contrast to white fat depots, in whichsome fat cells may be innervated but the principal sympa-thetic innervation is solely on blood vessels. In addition, ordi-nary lipocytes have only a single large droplet of white fat,whereas brown fat cells contain several small droplets of fat.Brown fat cells also contain many mitochondria. In thesemitochondria, an inward proton conductance that generatesATP takes places as usual, but in addition there is a secondproton conductance that does not generate ATP. This “short-circuit” conductance depends on a 32-kDa uncoupling pro-tein (UCP1). It causes uncoupling of metabolism and genera-tion of ATP, so that more heat is produced.PLASMA LIPIDS & LIPID TRANSPORTThe major lipids are relatively insoluble in aqueous solutionsand do not circulate in the free form. Free fatty acids (FFAs)are bound to albumin, whereas cholesterol, triglycerides, andphospholipids are transported in the form of lipoproteincomplexes. The complexes greatly increase the solubility ofthe lipids. The six families of lipoproteins (Table 1–5) aregraded in size and lipid content. The density of these lipopro-teins is inversely proportionate to their lipid content. Ingeneral, the lipoproteins consist of a hydrophobic core of tri-glycerides and cholesteryl esters surrounded by phospholipidsand protein. These lipoproteins can be transported from theintestine to the liver via an exogenous pathway, and betweenother tissues via an endogenous pathway.Dietary lipids are processed by several pancreatic lipases inthe intestine to form mixed micelles of predominantly FFA,2-monoglycerols, and cholesterol derivatives (see Chapter27). These micelles additionally can contain importantwater-insoluble molecules such as vitamins A, D, E, and K.These mixed micelles are taken up into cells of the intestinalTABLE 1–4. Lipids.Typical fatty acids:Triglycerides (triacylglycerols): Esters of glycerol and three fatty acids.R = Aliphatic chain of various lengths and degrees of saturation.Phospholipids:A. Esters of glycerol, two fatty acids, and 1. Phosphate = phosphatidic acid2. Phosphate plus inositol = phosphatidylinositol3. Phosphate plus choline = phosphatidylcholine (lecithin)4. Phosphate plus ethanolamine = phosphatidyl-ethanolamine(cephalin)5. Phosphate plus serine = phosphatidylserineB. Other phosphate-containing derivatives of glycerolC. Sphingomyelins: Esters of fatty acid, phosphate, choline, and the amino alcohol sphingosine.Cerebrosides: Compounds containing galactose, fatty acid, and sphin-gosine.Sterols: Cholesterol and its derivatives, including steroid hormones, bile acids, and various vitamins.Palmitic acid: CH5(CH2)14—C—OHOStearic acid: CH5(CH2)16—C—OHOOleic acid🙁Unsaturated)CH5(CH2)7CH=CH(CH2)7—C—OHOCH2—O—C—R CH2OHCHOH + 3HO—C—RCH2OHGlycerolOCH2—O—C—R + 3H2OCH2—O—C—RTriglycerideOOO
CHAPTER 1 General Principles & Energy Production in Medical Physiology 25FIGURE 1–26 Fatty acid oxidation. This process, splitting off two carbon fragments at a time, is repeated to the end of the chain.FIGURE 1–27 Formation and metabolism of ketone bodies. Note the two pathways for the formation of acetoacetate.OH + HS-CoA——OHH α,β-Unsaturated fatty acid–CoAβ-Keto fatty acid–CoAβ-Hydroxy fatty acid–CoA"Active" fatty acid + Acetyl–CoA——COH2O + R——OCH2CH2CH2CH2SRCoA + HS-CoA——CSCO——ORCH2CoA——CSC S CoA + CH3O——OR——COCH2CRMg2+ATP ADPFatty acidOxidizedflavoproteinReducedflavoprotein"Active" fatty acidCS CoAH2O + R——OCH CHC S CoACoANAD+ NADH + H+R = Rest of fatty acid chain.S——COCH3CoA + CH3S——COCoA2 Acetyl-CoA Acetoacetyl-CoA——COCH3CH2S——COCoA + HS-CoAβ-KetothiolaseCH2CCH3SCCoA + H2OAcetoacetyl-CoAAcetyl-CoA + Acetoacetyl-CoAHMG-CoA Acetoacetate + H++ Acetyl-CoAAcetoacetateAcetoacetateAcetone3-Hydroxy-3-methylglutaryl-CoA(HMG-CoA)β-HydroxybutyrateCH2—COHCH3CH2SCCoA + H+CH2–CO2CO2 + ATPCCH3O−CCH3CH3C + H+CH2CHOHCH3O−——CO + H+CCH3CH2O−CCOO−+ H++ HS-CoADeacylase(liver only)+2H –2HTissues except liver——O——O——O——O——O——O——O——O
26 SECTION I Cellular & Molecular Basis of Medical Physiologymucosa where large lipoprotein complexes, chylomicrons,are formed. The chylomicrons and their remnants constitutea transport system for ingested exogenous lipids (exogenouspathway). Chylomicrons can enter the circulation via thelymphatic ducts. The chylomicrons are cleared from the cir-culation by the action of lipoprotein lipase, which is locatedon the surface of the endothelium of the capillaries. Theenzyme catalyzes the breakdown of the triglyceride in thechylomicrons to FFA and glycerol, which then enter adiposecells and are reesterified. Alternatively, the FFA can remain inthe circulation bound to albumin. Lipoprotein lipase, whichrequires heparin as a cofactor, also removes triglyceridesfrom circulating very low density lipoproteins (VLDL).Chylomicrons depleted of their triglyceride remain in thecirculation as cholesterol-rich lipoproteins called chylomi-cron remnants, which are 30 to 80 nm in diameter. The rem-nants are carried to the liver, where they are internalized anddegraded.CLINICAL BOX 1–3 Diseases Associated with Imbalance of β-oxidation of Fatty AcidsKetoacidosis and even fatal. Three conditions lead to deficient intracellularglucose supplies, and hence to ketoacidosis: starvation; diabetesmellitus; and a high-fat, low-carbohydrate diet. The acetone odoron the breath of children who have been vomiting is due to theketosis of starvation. Parenteral administration of relatively smallamounts of glucose abolishes the ketosis, and it is for this reasonthat carbohydrate is said to be antiketogenic.Carnitine DeficiencyDeficient β-oxidation of fatty acids can be produced by carnitinedeficiency or genetic defects in the translocase or other enzymesinvolved in the transfer of long-chain fatty acids into the mito-chondria. This causes cardiomyopathy. In addition, it causes hy-poketonemic hypoglycemia with coma, a serious and oftenfatal condition triggered by fasting, in which glucose stores areused up because of the lack of fatty acid oxidation to provide en-ergy. Ketone bodies are not formed in normal amounts becauseof the lack of adequate CoA in the liver.The normal blood ketone level in humans is low (about 1mg/dL) and less than 1 mg is excreted per 24 h, because theketones are normally metabolized as rapidly as they areformed. However, if the entry of acetyl-CoA into the citric acidcycle is depressed because of a decreased supply of the prod-ucts of glucose metabolism, or if the entry does not increasewhen the supply of acetyl-CoA increases, acetyl-CoA accumu-lates, the rate of condensation to acetoacetyl-CoA increases,and more acetoacetate is formed in the liver. The ability of thetissues to oxidize the ketones is soon exceeded, and they accu-mulate in the bloodstream (ketosis). Two of the three ketonebodies, acetoacetate and β-hydroxybutyrate, are anions of themoderately strong acids acetoacetic acid and β-hydroxybutyricacid. Many of their protons are buffered, reducing the declinein pH that would otherwise occur. However, the bufferingcapacity can be exceeded, and the metabolic acidosis thatdevelops in conditions such as diabetic ketosis can be severeTABLE 1–5 The principal lipoproteins. Composition (%)Lipoprotein Size (nm) ProteinFree CholesterylCholesterol EstersTriglyceride Phospholipid OriginChylomicrons 75–1000 2 2 3 90 3 IntestineChylomicron remnants 30–80 … … … … … CapillariesVery low density lipoproteins (VLDL)30–80 8 4 16 55 17 Liver and intestineIntermediate-density lipo-proteins (IDL)25–40 10 5 25 40 20 VLDLLow-density lipoproteins (LDL)20 20 7 46 6 21 IDLHigh-density lipoproteins (HDL)7.5–10 50 4 16 5 25 Liver and intestine*The plasma lipids include these components plus free fatty acids from adipose tissue, which circulate bound to albumin.
CHAPTER 1 General Principles & Energy Production in Medical Physiology 27The endogenous system, made up of VLDL, intermedi-ate-density lipoproteins (IDL), low-density lipoproteins(LDL), and high-density lipoproteins (HDL), also trans-ports triglycerides and cholesterol throughout the body.VLDL are formed in the liver and transport triglyceridesformed from fatty acids and carbohydrates in the liver toextrahepatic tissues. After their triglyceride is largelyremoved by the action of lipoprotein lipase, they becomeIDL. The IDL give up phospholipids and, through the actionof the plasma enzyme lecithin-cholesterol acyltransferase(LCAT), pick up cholesteryl esters formed from cholesterolin the HDL. Some IDL are taken up by the liver. The remain-ing IDL then lose more triglyceride and protein, probably inthe sinusoids of the liver, and become LDL. LDL providecholesterol to the tissues. The cholesterol is an essential con-stituent in cell membranes and is used by gland cells to makesteroid hormones.FREE FATTY ACID METABOLISMIn addition to the exogenous and endogenous pathways de-scribed above, FFA are also synthesized in the fat depots inwhich they are stored. They can circulate as lipoproteins boundto albumin and are a major source of energy for many organs.They are used extensively in the heart, but probably all tissuescan oxidize FFA to CO2 and H2O.The supply of FFA to the tissues is regulated by twolipases. As noted above, lipoprotein lipase on the surface ofthe endothelium of the capillaries hydrolyzes the triglyc-erides in chylomicrons and VLDL, providing FFA and glyc-erol, which are reassembled into new triglycerides in the fatcells. The intracellular hormone-sensitive lipase of adiposetissue catalyzes the breakdown of stored triglycerides intoglycerol and fatty acids, with the latter entering the circula-tion. Hormone-sensitive lipase is increased by fasting andstress and decreased by feeding and insulin. Conversely,feeding increases and fasting and stress decrease the activityof lipoprotein lipase.CHOLESTEROL METABOLISMCholesterol is the precursor of the steroid hormones and bile ac-ids and is an essential constituent of cell membranes. It is foundonly in animals. Related sterols occur in plants, but plant sterolsare not normally absorbed from the gastrointestinal tract. Most ofthe dietary cholesterol is contained in egg yolks and animal fat.Cholesterol is absorbed from the intestine and incorporatedinto the chylomicrons formed in the intestinal mucosa. After thechylomicrons discharge their triglyceride in adipose tissue, thechylomicron remnants bring cholesterol to the liver. The liverand other tissues also synthesize cholesterol. Some of the choles-terol in the liver is excreted in the bile, both in the free form andas bile acids. Some of the biliary cholesterol is reabsorbed fromthe intestine. Most of the cholesterol in the liver is incorporatedinto VLDL and circulates in lipoprotein complexes.The biosynthesis of cholesterol from acetate is summarized inFigure 1–28. Cholesterol feeds back to inhibit its own synthesisby inhibiting HMG-CoA reductase, the enzyme that con-verts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)to mevalonic acid. Thus, when dietary cholesterol intake ishigh, hepatic cholesterol synthesis is decreased, and vice versa.However, the feedback compensation is incomplete, because adiet that is low in cholesterol and saturated fat leads to only amodest decline in circulating plasma cholesterol. The mosteffective and most commonly used cholesterol-lowering drugsare lovastatin and other statins, which reduce cholesterol syn-thesis by inhibiting HMG-CoA. The relationship between cho-lesterol and vascular disease is discussed in Clinical Box 1–4.ESSENTIAL FATTY ACIDSAnimals fed a fat-free diet fail to grow, develop skin and kidneylesions, and become infertile. Adding linolenic, linoleic, andarachidonic acids to the diet cures all the deficiency symptoms.These three acids are polyunsaturated fatty acids and becauseof their action are called essential fatty acids. Similar deficien-cy symptoms have not been unequivocally demonstrated inhumans, but there is reason to believe that some unsaturatedfats are essential dietary constituents, especially for children.FIGURE 1–28 Biosynthesis of cholesterol. Six mevalonic acid molecules condense to form squalene, which is then hydroxylated to cholesterol. The dashed arrow indicates feedback inhibition by cholesterol of HMG-CoA reductase, the enzyme that catalyzes meva-lonic acid formation.CH2CH3CH2COHHOOCCH2OHHOSqualene(C30H50)Mevalonic acid Cholesterol (C27H46O)3-Hydroxy-3-methylglutaryl-CoAAcetoacetyl-CoAAcetyl-CoAHMG-CoAreductaseAcetoacetateMevalonic acidSqualeneCholesterolAcetoacetate
28 SECTION I Cellular & Molecular Basis of Medical PhysiologyDehydrogenation of fats is known to occur in the body, but theredoes not appear to be any synthesis of carbon chains with the ar-rangement of double bonds found in the essential fatty acids.EICOSANOIDSOne of the reasons that essential fatty acids are necessary forhealth is that they are the precursors of prostaglandins, prosta-cyclin, thromboxanes, lipoxins, leukotrienes, and related com-pounds. These substances are called eicosanoids, reflectingtheir origin from the 20-carbon (eicosa-) polyunsaturated fat-ty acid arachidonic acid (arachidonate) and the 20-carbonderivatives of linoleic and linolenic acids. The prostaglandins are a series of 20-carbon unsaturatedfatty acids containing a cyclopentane ring. They were first iso-lated from semen but are now known to be synthesized in mostand possibly in all organs in the body. Prostaglandin H2(PGH2) is the precursor for various other prostaglandins,thromboxanes, and prostacyclin. Arachidonic acid is formedfrom tissue phospholipids by phospholipase A2. It is convertedto prostaglandin H2 (PGH2) by prostaglandin G/H synthases1 and 2. These are bifunctional enzymes that have both cyclo-oxygenase and peroxidase activity, but they are more com-monly known by the names cyclooxygenase 1 (COX1) andcyclooxygenase 2 (COX2). Their structures are very similar,but COX1 is constitutive whereas COX2 is induced by growthfactors, cytokines, and tumor promoters. PGH2 is converted toprostacyclin, thromboxanes, and prostaglandins by various tis-sue isomerases. The effects of prostaglandins are multitudinousand varied. They are particularly important in the femalereproductive cycle, in parturition, in the cardiovascular system,in inflammatory responses, and in the causation of pain. Drugsthat target production of prostaglandins are among the mostcommon over the counter drugs available (Clinical Box 1–5).Arachidonic acid also serves as a substrate for the produc-tion of several physiologically important leukotrienes andlipoxins. The leukotrienes, thromboxanes, lipoxins, andCLINICAL BOX 1–4 Cholesterol & AtherosclerosisThe interest in cholesterol-lowering drugs stems from therole of cholesterol in the etiology and course of athero-sclerosis. This extremely widespread disease predisposesto myocardial infarction, cerebral thrombosis, ischemicgangrene of the extremities, and other serious illnesses. It ischaracterized by infiltration of cholesterol and oxidizedcholesterol into macrophages, converting them into foamcells in lesions of the arterial walls. This is followed by acomplex sequence of changes involving platelets, macro-phages, smooth muscle cells, growth factors, and inflam-matory mediators that produces proliferative lesions whicheventually ulcerate and may calcify. The lesions distort thevessels and make them rigid. In individuals with elevatedplasma cholesterol levels, the incidence of atherosclerosisand its complications is increased. The normal range forplasma cholesterol is said to be 120 to 200 mg/dL, but inmen, there is a clear, tight, positive correlation between thedeath rate from ischemic heart disease and plasma choles-terol levels above 180 mg/dL. Furthermore, it is now clearthat lowering plasma cholesterol by diet and drugs slowsand may even reverse the progression of atherosclerotic le-sions and the complications they cause.In evaluating plasma cholesterol levels in relation to athero-sclerosis, it is important to analyze the LDL and HDL levels aswell. LDL delivers cholesterol to peripheral tissues, includingatheromatous lesions, and the LDL plasma concentration cor-relates positively with myocardial infarctions and ischemicstrokes. On the other hand, HDL picks up cholesterol from pe-ripheral tissues and transports it to the liver, thus loweringplasma cholesterol. It is interesting that women, who have alower incidence of myocardial infarction than men, havehigher HDL levels. In addition, HDL levels are increased in indi-viduals who exercise and those who drink one or two alco-holic drinks per day, whereas they are decreased in individualswho smoke, are obese, or live sedentary lives. Moderate drink-ing decreases the incidence of myocardial infarction, and obe-sity and smoking are risk factors that increase it. Plasma cho-lesterol and the incidence of cardiovascular diseases areincreased in familial hypercholesterolemia, due to variousloss-of-function mutations in the genes for LDL receptors.CLINICAL BOX 1–5 Pharmacology of ProstaglandinsBecause prostaglandins play a prominent role in the genesisof pain, inflammation, and fever, pharmacologists have longsought drugs to inhibit their synthesis. Glucocorticoids in-hibit phospholipase A2 and thus inhibit the formation of alleicosanoids. A variety of nonsteroidal anti-inflammatorydrugs (NSAIDs) inhibit both cyclooxygenases, inhibiting theproduction of PGH2 and its derivatives. Aspirin is the best-known of these, but ibuprofen, indomethacin, and others arealso used. However, there is evidence that prostaglandinssynthesized by COX2 are more involved in the production ofpain and inflammation, and prostaglandins synthesized byCOX1 are more involved in protecting the gastrointestinalmucosa from ulceration. Drugs such as celecoxib and rofe-coxib that selectively inhibit COX2 have been developed,and in clinical use they relieve pain and inflammation, possi-bly with a significantly lower incidence of gastrointestinal ul-ceration and its complications than is seen with nonspecificNSAIDs. However, rofecoxib has been withdrawn from themarket in the United States because of a reported increase ofstrokes and heart attacks in individuals using it. More re-search is underway to better understand all the effects of theCOX enzymes, their products, and their inhibitors.
CHAPTER 1 General Principles & Energy Production in Medical Physiology 29prostaglandins have been called local hormones. They haveshort half-lives and are inactivated in many different tissues.They undoubtedly act mainly in the tissues at sites in whichthey are produced. The leukotrienes are mediators of allergicresponses and inflammation. Their release is provoked whenspecific allergens combine with IgE antibodies on the surfacesof mast cells (see Chapter 3). They produce bronchoconstric-tion, constrict arterioles, increase vascular permeability, andattract neutrophils and eosinophils to inflammatory sites.Diseases in which they may be involved include asthma, pso-riasis, adult respiratory distress syndrome, allergic rhinitis,rheumatoid arthritis, Crohn’s disease, and ulcerative colitis.CHAPTER SUMMARY■ Cells contain approximately one third of the body fluids, while the remaining extracellular fluid is found between cells (intersti-tial fluid) or in the circulating blood plasma.■ The number of molecules, electrical charges, and particles of substances in solution are important in physiology.■ The high surface tension, high heat capacity, and high electrical ca-pacity allow H2O to function as an ideal solvent in physiology.■ Biological buffers including bicarbonate, proteins, and phos-phates can bind or release protons in solution to help maintain pH. Biological buffering capacity of a weak acid or base is great-est when pKa = pH.■ Fluid and electrolyte balance in the body is related to plasma os-molality. Isotonic solutions have the same osmolality as blood plasma, hypertonic have higher osmolality, while hypotonic have lower osmolality.■ Although the osmolality of solutions can be similar across a plasma membrane, the distribution of individual molecules and distribution of charge across the plasma membrane can be quite different. These are affected by the Gibbs-Donnan equilibrium and can be calculated using the Nernst potential equation.■ There is a distinct difference in concentration of ions in the extra-cellular and intracellular fluids (concentration gradient). The sep-aration of concentrations of charged species sets up an electrical gradient at the plasma membrane (inside negative). The electro-chemical gradient is in large part maintained by the Na, K ATPase.■ Cellular energy can be stored in high-energy phosphate com-pounds, including adenosine triphosphate (ATP). Coordinated oxidation-reduction reactions allow for production of a proton gradient at the inner mitochondrial membrane that ultimately yields to the production of ATP in the cell.■ Nucleotides made from purine or pyrimidine bases linked to ri-bose or 2-deoxyribose sugars with inorganic phosphates are the basic building blocks for nucleic acids, DNA, and RNA.■ DNA is a double-stranded structure that contains the funda-mental information for an organism. During cell division, DNA is faithfully replicated and a full copy of DNA is in every cell. The fundamental unit of DNA is the gene, which encodes infor-mation to make proteins in the cell. Genes are transcribed into messenger RNA, and with the help of ribosomal RNA and trans-fer RNAs, translated into proteins.■ Amino acids are the basic building blocks for proteins in the cell and can also serve as sources for several biologically active molecules. They exist in an “amino acid pool” that is derived from the diet, protein degradation, and de novo and resynthesis.■ Translation is the process of protein synthesis. After synthesis, proteins can undergo a variety of posttranslational modifica-tions prior to obtaining their fully functional cell state.■ Carbohydrates are organic molecules that contain equal amounts of C and H2O. Carbohydrates can be attached to pro-teins (glycoproteins) or fatty acids (glycolipids) and are critically important for the production and storage of cellular and body energy, with major supplies in the form of glycogen in the liver and skeletal muscle. The breakdown of glucose to generate en-ergy, or glycolysis, can occur in the presence or absence of O2 (aerobic or anaerobically). The net production of ATP during aerobic glycolysis is 19 times higher than anaerobic glycolysis. ■ Fatty acids are carboxylic acids with extended hydrocarbon chains. They are an important energy source for cells and their derivatives, including triglycerides, phospholipids and sterols, and have additional important cellular applications. Free fatty acids can be bound to albumin and transported throughout the body. Triglycerides, phospholipids, and cholesterol are trans-ported as lipoprotein complexes.MULTIPLE-CHOICE QUESTIONS For all questions, select the single best answer unless otherwise directed.1. The membrane potential of a particular cell is at the K+ equilib-rium. The intracellular concentration for K+ is at 150 mmol/L and the extracellular concentration for K+ is at 5.5 mmol/L. What is the resting potential?A) –70 mvB) –90 mvC) +70 mvD) +90 mv2. The difference in concentration of H+ in a solution of pH 2.0 compared with one of pH 7.0 isA) 5-fold.B) ⅕ as much.C) 105 fold.D) 10–5 as much.3. Transcription refers toA) the process where an mRNA is used as a template for protein production.B) the process where a DNA sequence is copied into RNA for the purpose of gene expression.C) the process where DNA wraps around histones to form a nucleosome.D) the process of replication of DNA prior to cell division.4. The primary structure of a protein refers toA) the twist, folds, or twist and folds of the amino acid sequence into stabilized structures within the protein (ie, α-helices and β-sheets).B) the arrangement of subunits to form a functional structure.C) the amino acid sequence of the protein.D) the arrangement of twisted chains and folds within a protein into a stable structure.
