Porphyrins And Bile Pigments PDF

C H A P T E R Porphyrins & Bile Pigments Victor W. Rodwell, PhD OBJ E C TI VE S 31 Write the structural uormulas ou the tw...

C H A P T E R Porphyrins & Bile Pigments Victor W. Rodwell, PhD OBJ E C TI VE S 31 Write the structural uormulas ou the two amphibolic intermediates whose condensation initiates heme biosynthesis. After studying this chapter, Identiuy the enzyme that catalyzes the key regulated step ou hepatic heme you should be able to: biosynthesis. Explain why, although porphyrinogens and porphyrins both are tetrapyrroles, porphyrins are colored whereas porphyrinogens are colorless. Speciuy the intracellular locations ou the enzymes and metabolites ou heme biosynthesis. Outline the causes and clinical presentations ou various porphyrias. Identiuy the roles ou heme oxygenase and ou UDP-glucosyl transuerase in heme catabolism. Defne jaundice, name some ou its causes, and suggest how to determine its biochemical basis. Speciuy the biochemical basis ou the clinical laboratory terms “direct bilirubin” and “indirect bilirubin.” BIOMEDICAL IMPORTANCE pyrrole rings. Examples include iron porphyrins such as the heme ow hemoglobin and the magnesium-containing porphy- vhe biochemistry ow the porphyrins and ow the bile pig- rin chlorophyll, the photosynthetic pigment ow plants. Heme ments are closely related topics. Heme is synthesized wrom proteins are ubiquitous in biology and serve diverse wunctions porphyrins and iron, and the products ow degradation ow including, but not limited to, oxygen transport and storage heme include the bile pigments and iron. vhe biochemistry ow (eg, hemoglobin and myoglobin) and electron transport (eg, the porphyrins and ow heme is basic to understanding the cytochrome c and cytochrome P450). Hemes are tetrapyr- varied wunctions ow hemoproteins, and the porphyrias, roles, ow which two types, heme b and heme c, predominate a group ow diseases caused by abnormalities in the pathway (Figure 31–2). In heme c the vinyl groups ow heme b are ow porphyrin biosynthesis. A much more common clinical replaced by covalent thioether links to an apoprotein, typically condition is jaundice, a consequence ow an elevated level ow via cysteinyl residues. Unlike heme b, heme c thus does not plasma bilirubin, due either to overproduction ow bilirubin readily dissociate wrom its apoprotein. or to wailure ow its excretion. Jaundice occurs in numerous Proteins that contain heme are widely distributed in nature diseases ranging wrom hemolytic anemias to viral hepatitis (Table 31–1). Vertebrate heme proteins generally bind one and to cancer ow the pancreas. mole ow heme c per mole, although those ow nonvertebrates may bind signiwicantly more heme. PORPHYRINS Porphyrins are cyclic compounds wormed by the linkage HEME IS SYNTHESIZED FROM ow wour pyrrole rings through methyne (—— HC—) bridges (Figure 31–1). Various side chains can replace the eight SUCCINYL-CoA & GLYCINE numbered hydrogen atoms ow the pyrrole rings. vhe biosynthesis ow heme involves both cytosolic and mito- Porphyrins can worm complexes with metal ions that worm chondrial reactions and intermediates. Heme biosynthesis coordinate bonds to the nitrogen atom ow each ow the wour h t t p s :// a l l e b o o k s t o r e s. c o m occurs in most mammalian cells except mature erythrocytes, 315 316 SECTION VI Metabolism ou Proteins & Amino Acids TABLE 31–1 Examples of Important Heme Proteinsa Protein Function Hemoglobin Transport ou oxygen in blood Myoglobin Storage ou oxygen in muscle Cytochrome c Involvement in the electron transport chain Cytochrome P450 Hydroxylation ou xenobiotics Catalase Degradation ou hydrogen peroxide Tryptophan pyrrolase Oxidation ou tryptophan a The uunctions ou the above proteins are described in various chapters ou this text. Following the exit ow δ-aminolevulinate into the cytosol, the reaction catalyzed by cytosolic ALA dehydratase (EC 4.2.1.24; porphobilinogen synthase) condenses two molecules ow ALA, worming porphobilinogen: FIGURE 31–1 The porphyrin molecule. Rings are labeled I, II, III, and IV. Substituent positions are labeled 1 through 8. The uour (2) 2 δ-Aminolevulinate → porphobilinogen + 2 H2O methyne bridges (=HC—) are labeled α, β, γ, and δ. (Figure 31–4). A zinc metalloprotein, ALA dehydratase is sensitive to inhibition by lead, as can occur in lead poisoning. which lack mitochondria. Approximately 85% ow heme syn- vhe third reaction, catalyzed by cytosolic hydroxymethyl- thesis occurs in erythroid precursor cells in the bone mar- bilane synthase (uroporphyrinogen I synthase, EC 2.5.1.61) row, and the majority ow the remainder in hepatocytes. Heme involves head-to-tail condensation ow wour molecules ow por- biosynthesis is initiated by the condensation ow succinyl-CoA phobilinogen to worm the linear tetrapyrrole hydroxymethyl- and glycine in a pyridoxal phosphate-dependent reaction cat- bilane (Figure 31–5, top): alyzed by mitochondrial δ-aminolevulinate synthase (ALA (3) 4 Porphobilinogen + H2O → hydroxymethylbilane + 4 NH3 synthase, EC 2.3.1.37). Subsequent cyclization ow hydroxymethylbilane, catalyzed (1) Succinyl-CoA + glycine → δ-aminolevulinate by cytosolic uroporphyrinogen III synthase, EC 4.2.1.75: + CoA-SH + CO2 (4) Hydroxymethylbilane → uroporphyrinogen III + H2O Humans express two isozymes ow ALA synthase. ALAS1 is ubiquitously expressed throughout the body, whereas ALAS2 worms uroporphyrinogen III (Figure 31–5, bottom right). is expressed in erythrocyte precursor cells. Formation ow Hydroxymethylbilane can undergo spontaneous cyclization δ-aminolevulinate is rate-limiting wor porphyrin biosynthesis worming uroporphyrinogen I (Figure 31–5, bottom left), in mammalian liver (Figure 31–3). but under normal conditions, the uroporphyrinogen wormed is almost exclusively the type III isomer. vhe type I isomers ow porphyrinogens are, however, wormed in excess in certain porphyrias. Since the pyrrole rings ow these uroporphyrino- gens are connected by methylene (—CH2—) rather than by Cys S Cys S N N N N Fe Fe N N N N O OH OH O OH OH O O heme b heme c FIGURE 31–3 Synthesis of δ-aminolevulinate (ALA). This FIGURE 31–2 Structures of heme b and heme c. mitochondrial reaction is catalyzed by ALA synthase.  CHAPTER 31 Porphyrins & Bile Pigments 317 A P M P I Uroporphyrinogen I A A decarboxylase M M IV II IV II P III P P III P 4CO2 P A P M Uroporphyrinogen III Coproporphyrinogen III FIGURE 31–6 Decarboxylation of uroporphyrinogen III to coproporphyrinogen III. Shown is a representation ou the tetrapyr- role to emphasize the conversion ou uour attached acetyl groups to FIGURE 31–4 Formation of porphobilinogen. Cytosolic por- methyl groups. (A, acetyl; M, methyl; P, propionyl.) phobilinogen synthase converts two molecules ou δ-aminolevulinate to porphybilinogen. All wour acetate moieties ow uroporphyrinogen III next undergo decarboxylation to methyl (M) substituents, worming methyne bridges (— — HC—), the double bonds do not worm a coproporphyrinogen III in a cytosolic reaction catalyzed by conjugated system. Porphyrinogens thus are colorless. vhey uroporphyrinogen decarboxylase, EC 4.1.1.37 (Figure 31–6): are, however, readily auto-oxidized to colored porphyrins. (5) Uroporphyrinogen III → coproporphyrinogen III + 4 CO2 vhis decarboxylase can also convert uroporphyrinogen I, iw A HOOC COOH present, to coproporphyrinogen I. P H 2C CH 2 vhe winal three reactions ow heme biosynthesis all occur in CH 2 mitochondria. Coproporphyrinogen III enters the mitochon- C C dria and is converted, successively, to protoporphyrinogen III, C CH and then to protoporphyrin III. vhese reactions are catalyzed H 2C N by coproporphyrinogen oxidase (EC 1.3.3.3), which decar- NH 2 H boxylates and oxidizes the two propionic acid side chains to Four molecules of worm protoporphyrinogen III: porphobilinogen (6) Coproporphyrinogen III + O2 + 2 H+ → Uroporphyrinogen I 4 NH 3 synthase protoporphyrinogen III + 2 CO2 + 2 H2O Hydroxymethylbilane vhis oxidase is speciwic wor type III coproporphyrinogen, (linear tetrapyrrole) so type I protoporphyrins generally do not occur in humans. Spontaneous Uroporphyrinogen III Protoporphyrinogen III is next oxidized to protoporphyrin cyclization synthase III in a reaction catalyzed by protoporphyrinogen oxidase, EC 1.3.3.4: A P A P A P A P (7) Protoporphyrinogen III + 3 O2 → protoporphyrin III C C H2 C C C C C H2 C C C + 3 H2O2 I II I II C C C C C C C C N N N N vhe eighth and winal step in heme synthesis involves the CH 2 H H CH 2 CH 2 H H CH 2 incorporation ow werrous iron into protoporphyrin III in a reac- H H H H tion catalyzed by ferrochelatase (heme synthase, EC 4.99.1.1), N N N N (Figure 31–7): C C C C C C C C IV III IV III C C C C H2 C C C C H2 C C (8) Protoporphyrin III + Fe2+ → heme + 2 H+ P A P A A P P A Figure 31–8 summarizes the stages ow the biosynthesis ow the Type I Type III uroporphyrinogen uroporphyrinogen porphyrin derivatives wrom porphobilinogen. For the above reactions, numbers correspond to those in Figure 31–8 and FIGURE 31–5 Synthesis of hydroxymethylbilane and its in Table 31–2. subsequent cyclization to porphobilinogen III. Cytosolic hydroxy- methylbilane synthase (ALA dehydratase) uorms a linear tetrapyrrole, which cytosolic uroporphyrinogen synthase cyclizes to uorm uropor- ALA Synthase Is the Key Regulatory phyrinogen III. Notice the asymmetry ou the substituents on ring Enzyme in Hepatic Biosynthesis of Heme h t t p s :// a l l e b o o kUnlike s t oALAS2, r e which s. cis oexpressed m exclusively in erythrocyte 4, so that the highlighted acetate and propionate substituents are reversed in uroporphyrinogens I and III. (A, acetate [—CH2COO–]; P, propionate [—CH2CH2COO–].) precursor cells, ALAS1 is expressed throughout body tissues. 318 SECTION VI Metabolism ou Proteins & Amino Acids Porphobilinogen Uroporphyrinogen I synthase Hydroxymethylbilane Uroporphyrinogen III synthase Spontaneous 6H 6H Uroporphyrin III Uroporphyrinogen III Uroporphyrinogen I Uroporphyrin I Light Light Cytosol Uroporphyrinogen 6H decarboxylase 6H 4CO 2 4CO 2 Coproporphyrin III Coproporphyrinogen III Coproporphyrinogen I Coproporphyrin I Light Light Coproporphyrinogen oxidase Protoporphyrinogen III Mitochondria Protoporphyrinogen Or light in vitro oxidase 6H Protoporphyrin III Fe2+ Ferrochelatase Heme FIGURE 31–7 Biosynthesis from porphobilinogen of the indicated porphyrin derivatives. vhe reaction catalyzed by ALA synthase 1 (Figure 31–3) is absorption and wluorescence spectra. vhe visible and the rate-limiting wor biosynthesis ow heme in liver. vypically wor an ultraviolet spectra ow porphyrins and porphyrin derivatives enzyme that catalyzes a rate-limiting reaction, ALAS1 has a are usewul wor their identiwication (Figure 31–9). vhe sharp short halw-liwe. Heme, acting through the Erg-1 aporepressor absorption band near 400 nm, a distinguishing weature shared and one ow its NAB corepressors, acts as a negative regulator by all porphyrins, is termed the Soret band awter its discoverer, ow the synthesis ow ALAS1 (Figure 31–8). Synthesis ow ALAS1 the French physicist Charles Soret. thus increases greatly in the absence ow heme, but diminishes Porphyrins dissolved in strong mineral acids or in organic in its presence. Heme also awwects translation ow ALAS1 and solvents and illuminated by ultraviolet light emit a strong red its translocation wrom its cytosolic site ow synthesis into the fluorescence, a property owten used to detect small amounts mitochondrion. Many drugs whose metabolism requires the ow wree porphyrins. vhe photodynamic properties ow porphy- hemoprotein cytochrome P450 increase cytochrome P450 rins have suggested their possible use in the treatment ow cer- biosynthesis. vhe resulting depletion ow the intracellular heme tain types ow cancer, a procedure called cancer phototherapy. pool induces synthesis ow ALAS1, and the rate ow heme syn- Since tumors owten take up more porphyrins than do normal thesis rises to meet metabolic demand. By contrast, since tissues, hematoporphyrin or related compounds are admin- ALAS2 is not weedback regulated by heme, its biosynthesis is istered to a patient with an appropriate tumor. vhe tumor is not induced by these drugs. then exposed to an argon laser to excite the porphyrins, pro- ducing cytotoxic ewwects. PORPHYRINS ARE Spectrophotometry Is Used to Detect COLORED & FLUORESCE Porphyrins & Their Precursors While porphyrinogens are colorless, the various porphyrins Coproporphyrins and uroporphyrins are excreted in increased are colored. vhe conjugated double bonds in the pyrrole amounts in the porphyrias. When present in urine or weces, they rings and linking methylene groups ow porphyrins (absent in can be separated by extraction with appropriate solvents, then the porphyrinogens) are responsible wor their characteristic identiwied and quantiwied using spectrophotometric methods.  CHAPTER 31 Porphyrins & Bile Pigments 319 Hemoproteins Proteins Heme Aporepressor 8. Ferrochelatase Fe 2 + Protoporphyrin III 7. Protoporphyrinogen oxidase Protoporphyrinogen III 6. Coproporphyrinogen oxidase Coproporphyrinogen III 5. Uroporphyrinogen decarboxylase Uroporphyrinogen III 4. Uroporphyrinogen III synthase Hydroxymethylbilane 3. Uroporphyrinogen I synthase Porphobilinogen 2. ALA dehydratase ALA 1. ALA synthase – Succinyl-CoA + Glycine FIGURE 31–8 Intermediates, enzymes, and regulation of heme synthesis. The numbers ou the enzymes that catalyze the indicated reactions are those used in the accompanying text and in column 1 ou Table 31–2. Enzymes 1, 6, 7, and 8 are mitochondrial, but enzymes 2 to 5 are cytosolic. Regulation ou hepatic heme synthesis occurs at ALA synthase (ALAS1) by a repression–derepression mechanism mediated by heme and a hypothetical aporepressor (not shown). Mutations in the gene encoding enzyme 1 cause X-linked sideroblastic anemia. Mutations in the genes encoding enzymes 2 to 8 give rise to the porphyrias. DISORDERS OF HEME 1. Similar or identical clinical signs and symptoms can arise wrom diwwerent mutations in genes that encode either a given BIOSYNTHESIS enzyme or an enzyme that catalyzes a successive reaction. Disorders ow heme biosynthesis may be genetic or acquired. 2. Rational therapy requires an understanding ow the bio- An example ow an acquired dewect is lead poisoning. Lead can chemistry ow the enzyme-catalyzed reactions in both nor- inactivate werrochelatase and ALA dehydratase by complexing mal and impaired individuals. with essential thiol groups. Signs include elevated levels ow 3. Identiwication ow the intermediates and side products that protoporphyrin in erythrocytes and elevated urinary levels ow accumulate prior to a metabolic block can provide the ALA and coproporphyrin. basis wor metabolic screening tests that can implicate the Genetic disorders ow heme metabolism and ow bilirubin impaired reaction. metabolism (see below) share the wollowing weatures with met- 4. Dewinitive diagnosis involves quantitative assay ow the activ- h t t p s :// a l l e b o o k s t o r e s. c o m abolic disorders ow urea biosynthesis (see Chapter 28): ity ow the enzyme(s) suspected to be dewective. vo this might 320 SECTION VI Metabolism ou Proteins & Amino Acids TABLE 31–2 Summary of Major Findings in the Porphyriasa Enzyme Involvedb Type, Class, and OMIM Number Major Signs and Symptoms Results of Laboratory Tests 1. ALA synthase 2 (ALAS2), X-linked sideroblasticanemiac Anemia Red cell counts and hemoglobin EC 2.3.1.37 (erythropoietic) (OMIM 301300) decreased 2. ALA dehydratase EC 4.2.1.24 ALA dehydratase defciency Abdominal pain, neuropsychiatric Urinary ALA and coproporphyrin (hepatic) (OMIM 125270) symptoms III increased 3. Uroporphyrinogen I synthased Acute intermittent porphyria Abdominal pain, neuropsychiatric Urinary ALA and PBGe increased EC 2.5.1.61 (hepatic) (OMIM 176000) symptoms 4. Uroporphyrinogen III synthase Congenital erythropoietic Photosensitivity Urinary, uecal, and red cell EC 4.2.1.75 (erythropoietic) (OMIM 263700) uroporphyrin I increased 5. Uroporphyrinogen Porphyria cutaneatarda (hepatic) Photosensitivity Urinary uroporphyrin I increased decarboxylase EC 4.1.1.37 (OMIM 176100) 6. Coproporphyrinogen oxidase Hereditary coproporphyria Photosensitivity, abdominal pain, Urinary ALA, PBG, and EC 1.3.3.3 (hepatic) (OMIM 121300) neuropsychiatric symptoms coproporphyrin III and uecal coproporphyrin III increased 7. Protoporphyrinogen oxidase Variegate porphyria (hepatic) Photosensitivity, abdominal pain, Urinary ALA, PBG, and EC 1.3.3.4 (OMIM 176200) neuropsychiatric symptoms coproporphyrin III and uecal protoporphyrin IX increased 8. Ferrochelatase EC 4.99.1.1 Protoporphyria (erythropoietic) Photosensitivity Fecal and red cell protoporphyrin (OMIM 177000) IX increased a Only the biochemical uindings in the active stages ou these diseases are listed. Certain biochemical abnormalities are detectable in the latent stages ou some ou the above condi- tions. Conditions 3, 5, and 8 are generally the most prevalent porphyrias. Condition 2 is rare. b The numbering ou the enzymes in this Table corresponds to that used in Figure 31–8. c X-linkedsideroblastic anemia is not a porphyria but is included here because ALA synthase is involved. d This enzyme is also called PBG deaminase or hydroxymethylbilane synthase. e PBG = porphyrobilinogen III. Abbreviations: ALA, δ-aminolevulinic acid; PBG, porphobilinogen. be added consideration ow the as yet incompletely identiwied wrom the accumulation ow metabolites prior to the block. wactors that wacilitate translocation ow enzymes and inter- vable 31–2 lists six major types ow porphyria that rewlect low mediates between cellular compartments. or absent activity ow enzymes that catalyze reactions 2 through 5. Comparison ow the DNA sequence ow the gene that encodes 8 ow Figure 31–8. Possibly due to potential lethality, there is no a given mutant enzyme to that ow the wild-type gene can known dewect ow ALAS1. Individuals with low ALAS2 activ- identiwy the speciwic mutation(s) that cause the disease. ity develop anemia, not porphyria (vable 31–2). Porphyria consequent to low activity ow ALA dehydratase, termed ALA dehydratase-dewicient porphyria, is extremely rare. The Porphyrias vhe signs and symptoms ow porphyria result either wrom a Congenital Erythropoietic Porphyria deficiency ow intermediates beyond the enzymatic block, or While most porphyrias are inherited in an autosomal dominant manner, congenital erythropoietic porphyria is inherited in a recessive mode. vhe dewective enzyme in congenital erythropoi- etic porphyria is uroporphyrinogen III synthase (Figure 31–5, 5 bottom). vhe photosensitivity and severe diswigurement exhib- ited by some victims ow congenital erythropoietic porphyria has Log absorbency 4 suggested them as prototypes ow so-called werewolves. 3 Acute Intermittent Porphyria 2 vhe dewective enzyme in acute intermittent porphyria is 1 hydroxymethylbilane synthase (Figure 31–5, bottom). ALA and porphobilinogen accumulate in body tissues and wluids (Figure 31–10). 300 400 500 600 700 Wavelength (nm) Subsequent Metabolic Blocks FIGURE 31–9 Absorption spectrum of hematoporphyrin. The Blocks later in the pathway result in the accumulation of spectrum is ou a dilute (0.01%) solution ou hematoporphyrin in 5% HCl. the porphyrinogens indicated in Figures 31–8 and 31–10.  CHAPTER 31 Porphyrins & Bile Pigments 321 ow hematin to repress ALAS1 synthesis to diminish production Mutations in various genes ow harmwul heme precursors. Patients exhibiting photosensi- tivity benewit wrom sunscreens and possibly wrom administered Abnormalities of the β-carotene, which appears to lessen production ow wree radi- enzymes of heme synthesis cals, decreasing photosensitivity. Accumulation of ALA and PBG and/or Accumulation of CATABOLISM OF HEME porphyrinogens in skin decrease in heme in cells and body fluids and tissues PRODUCES BILIRUBIN Human adults normally destroy about 200 billion erythrocytes per day. A 70-kg human therewore turns over approximately Spontaneous oxidation Neuropsychiatric signs of porphyrinogens to 6 g of hemoglobin daily. All products are reused. vhe globin and symptoms porphyrins is degraded to its constituent amino acids, and the released iron enters the iron pool. vhe iron-wree porphyrin portion ow heme is also degraded, mainly in the reticuloendothelial cells Photosensitivity ow the liver, spleen, and bone marrow. vhe catabolism ow heme wrom all heme proteins takes FIGURE 31–10 Biochemical basis of the major signs and place in the microsomal fraction ow cells by heme oxygenase, symptoms of the porphyrias. EC 1.14.18.18. Heme oxygenase synthesis is substrate-inducible, and heme also serves both as a substrate and as a cowactor wor vheir oxidation to the corresponding porphyrin derivatives the reaction. vhe iron ow the heme that reaches heme oxy- cause photosensitivity to visible light ow about 400-nm genase has usually been oxidized to its ferric form (hemin). wavelength. Possibly as a result ow their excitation and reaction Conversion ow one mole ow heme-Fe3+ to biliverdin, carbon with molecular oxygen, the resulting oxygen radicals injure monoxide, and Fe3+ consumes three moles ow O2, plus seven lysosomes and other subcellular organelles, releasing proteolytic electrons provided by NADH and NADPH–cytochrome P450 enzymes that cause variable degrees ow skin damage, including reductase: scarring. Fe3+-Heme + 3 O2 + 7 e– → biliverdin + CO + Fe3+ CLASSIFICATION OF THE Despite its high awwinity wor heme-Fe2+ (see Chapter 6), the carbon monoxide produced does not severely inhibit heme PORPHYRIAS oxygenase. Birds and amphibians excrete the green-colored bili- Porphyrias may be termed erythropoietic or hepatic based verdin directly. In humans, biliverdin reductase (EC 1.3.1.24) on the organs most awwected, typically bone marrow and the reduces the central methylene bridge ow biliverdin to a methyl liver (vable 31–2). Diwwerent and variable levels ow heme, toxic group, producing the yellow-pigment bilirubin (Figure 31–11): precursors, or metabolites probably account wor why spe- Biliverdin + NADPH + H+ → bilirubin + NADP+ ciwic porphyrias diwwerentially awwect some cell types and organs. Alternatively, porphyrias may be classiwied as acute Since 1 g ow hemoglobin yields about 35 mg ow bilirubin, or cutaneous based on their clinical weatures. vhe diagnosis ow human adults form 250 to 350 mg of bilirubin per day. vhis a speciwic type ow porphyria involves consideration ow the clini- is derived principally wrom hemoglobin, and also wrom inewwec- cal and wamily history, physical examination, and appropriate tive erythropoiesis and wrom catabolism ow other heme proteins. laboratory tests. vable 31–2 lists the major signs, symptoms, Conversion ow heme to bilirubin by reticuloendothe- and relevant laboratory windings in the six principal types ow lial cells can be observed visually as the purple color ow the porphyria. heme in a hematoma slowly converts to the yellow pigment ow bilirubin. Drug-Induced Porphyria Certain drugs (eg, barbiturates, griseowulvin) induce the produc- Bilirubin Is Transported to the Liver tion ow cytochrome P450. In patients with porphyria, this can Bound to Serum Albumin precipitate an attack ow porphyria by depleting heme levels. vhe Bilirubin is only sparingly soluble in water. Consequently, it compensating derepression ow synthesis ow ALAS1 then results must be bound to serum albumin wor transport to the liver. in increased levels ow potentially harmwul heme precursors. Albumin appears to have both high-awwinity and low-awwinity sites wor bilirubin. vhe high-awwinity site can bind approxi- Possible Treatments for Porphyrias mately 25 mg ow bilirubin/100 mL ow plasma. More loosely Present treatment ow porphyrias is essentially symptomatic: bound bilirubin can readily be detached and diwwused into h t t p s :// a l l e b o o k s t o r e s. c o m avoiding drugs that induce production ow cytochrome P450, ingestion ow large amounts ow carbohydrate, and administration tissues, and antibiotics and certain other drugs can compete with and displace bilirubin wrom albumin’s high-awwinity site. 322 SECTION VI Metabolism ou Proteins & Amino Acids COOH COOH facilitated transport system. Even under pathologic condi- tions, transport does not appear to be rate-limiting wor the metabolism ow bilirubin. vhe net uptake ow bilirubin depends on its removal by subsequent metabolism. Once internal- ized, bilirubin binds to cytosolic proteins such as glutathione N N S-transwerase, previously known as a ligandin, to prevent bili- Fe3+ rubin wrom reentering the bloodstream. N N Conjugation of Bilirubin With Glucuronate Ferric heme Bilirubin is nonpolar, and would persist in cells (eg, bound to lipids) iw not converted to a more water-soluble worm. Bili- 3O2 + 7e– rubin is converted to a more polar molecule by conjugation with glucuronic acid (Figure 31–12). A bilirubin-speciwic CO + Fe3+ UDP-glucuronosyltransferase (EC 2.4.1.17) ow the endoplas- mic reticulum catalyzes stepwise transwer to bilirubin ow two HOOC COOH glucosyl moieties wrom UDP-glucuronate: Bilirubin + UDP-glucuronate → bilirubin monoglucuronide + UDP Bilirubin monoglucuronide + UDP-glucuronate → bilirubin diglucuronide + UDP O N N N N O H H H Biliverdin Secretion of Bilirubin Into the Bile Secretion ow conjugated bilirubin into the bile occurs by an NADPH Biliverdin active transport mechanism, which probably is rate-limiting wor the entire process ow hepatic bilirubin metabolism. vhe Reductase NADP + protein involved is a multispecific organic anion trans- porter (MOAT) located in the plasma membrane ow the bile canaliculi. A member ow the wamily ow AvP-binding cassette HOOC COOH transporters, MOAv transports a number ow organic anions. vhe hepatic transport ow conjugated bilirubin into the bile is inducible by the same drugs that can induce the conjugation ow bilirubin. Conjugation and excretion ow bilirubin thus con- O N N N N O stitute a coordinated wunctional unit. H H H H Most ow the bilirubin excreted in the bile ow mammals is Bilirubin bilirubin diglucuronide. Bilirubin UDP-glucuronosyltranswer- ase activity can be induced by several drugs, including pheno- FIGURE 31–11 Conversion of ferric heme to biliverdin, and then to bilirubin. (1) Conversion ou uerric heme to biliverdin is cata- barbital. However, when bilirubin conjugates exist abnormally lyzed by the heme oxygenase system. (2) Subsequently, biliverdin in human plasma (eg, in obstructive jaundice), they are pre- reductase reduces bilirubin to bilirubin. dominantly monoglucuronides. Figure 31–13 summarizes Further Metabolism of Bilirubin Occurs O O Primarily in the Liver – OOC(CH2O)4C O C C O C(CH2O)4COO– Hepatic catabolism ow bilirubin takes place in three stages: H2C CH2 uptake by the liver, conjugation with glucuronic acid, and H2 C CH2 M V M M M V secretion in the bile. II III IV I O C C C O Uptake of Bilirubin by Liver Parenchymal Cells FIGURE 31–12 Bilirubin diglucuronide. Glucuronate moi- eties are attached via ester bonds to the two propionate groups ou Bilirubin is removed wrom albumin and taken up at the sinu- bilirubin. Clinically, the diglucuronide is also termed “direct reacting” soidal surwace ow hepatocytes by a large capacity, saturable bilirubin.  CHAPTER 31 Porphyrins & Bile Pigments 323 Blood presence ow added methanol measures total bilirubin. vhe Bilirubin Albumin difference between total bilirubin and direct bilirubin is known as “indirect bilirubin,” and is unconjugated bilirubin. 1. UPTAKE HYPERBILIRUBINEMIA Hepatocyte Bilirubin CAUSES JAUNDICE 2. CONJUGATION Hyperbilirubinemia, a blood level that exceeds 1 mg ow biliru- Neonatal jaundice bin per dL (17 μmol/L), may result wrom production ow more UDP-GlcUA “Toxic” jaundice UDP-GlcUA Crigler-Najjar syndrome bilirubin than the normal liver can excrete, or wrom the wailure Gilbert syndrome ow a damaged liver to excrete normal amounts ow bilirubin. In the absence ow hepatic damage, obstruction ow the excretory Bilirubin diglucuronide ducts ow the liver prevents the excretion ow bilirubin, and will also cause hyperbilirubinemia. In all these situations, when 3. SECRETION Dubin-Johnson syndrome the blood concentration ow bilirubin reaches 2 to 2.5 mg/dL, it diwwuses into the tissues, which turn yellow, a condition termed jaundice or icterus. Bile ductule Bilirubin diglucuronide Occurrence of Unconjugated Bilirubin in Blood FIGURE 31–13 Diagrammatic representation of the three Forms ow hyperbilirubinemia include retention hyperbiliru- major processes (uptake, conjugation, and secretion) involved in the transfer of bilirubin from blood to bile. Certain proteins ou binemia due to overproduction ow bilirubin, and regurgita- hepatocytes bind intracellular bilirubin and may prevent its euulux tion hyperbilirubinemia due to rewlux into the bloodstream into the bloodstream. The processes auuected in certain conditions because ow biliary obstruction. that cause jaundice are also shown. Because ow its hydrophobicity, only unconjugated bilirubin can cross the blood–brain barrier into the central nervous sys- the three major processes involved in the transwer ow bilirubin tem. Encephalopathy due to hyperbilirubinemia (kernicterus) wrom blood to bile. Sites that are awwected in a number ow condi- thus occurs only with unconjugated bilirubin, as in retention tions causing jaundice are also indicated. hyperbilirubinemia. Alternatively, because ow its water solubil- ity, only conjugated bilirubin can appear in urine. Accordingly, Intestinal Bacteria Reduce Conjugated choluric jaundice (choluria is the presence ow bile pigments Bilirubin to Urobilinogen in the urine) occurs only in regurgitation hyperbilirubine- When conjugated bilirubin reaches the terminal ileum and mia, and acholuric jaundice occurs only in the presence ow an the large intestine, the glucuronosyl moieties are removed by excess ow unconjugated bilirubin. Table 31–3 lists some causes speciwic bacterial β-glucuronidases (EC 3.2.1.31). Subsequent ow unconjugated and conjugated hyperbilirubinemia. A mod- reduction by the wecal wlora worms a group ow colorless tetra- erate hyperbilirubinemia accompanies hemolytic anemias. pyrroles called urobilinogens. Small portions ow urobilino- gens are reabsorbed in the terminal ileum and large intestine TABLE 31–3 Some Causes of Unconjugated and and subsequently are reexcreted via the enterohepatic urobi- Conjugated Hyperbilirubinemia linogen cycle. Under abnormal conditions, particularly when excessive bile pigment is wormed or when liver disease disrupts Unconjugated Conjugated this intrahepatic cycle, urobilinogen may also be excreted in Hemolytic anemias Obstruction ou the biliary tree the urine. Most ow the colorless urobilinogens wormed in the Neonatal “physiological Dubin–Johnson syndrome colon are oxidized there to colored urobilins and excreted in jaundice” the weces. Fecal darkening upon standing in air results wrom Crigler-Najjar syndromes types I Rotor syndrome the oxidation ow residual urobilinogens to urobilins. and II Gilbert syndrome Liver diseases such as the Measurement of Bilirubin in Serum various types ou hepatitis Quantitation ow bilirubin employs a colorimetric method Toxic hyperbilirubinemia based on the reddish-purple color wormed when bilirubin reacts with diazotized sulwanilic acid. An assay conducted in These causes are discussed brieuly in the text. Common causes ou obstruction ou the biliary tree are a stone in the common bile duct and cancer ou the head ou the pan- the absence ow added methanol measures “direct bilirubin,” h t t p s :// a l l e b o o k s t o r e s. c o m creas. Various liver diseases (eg, the various types ou hepatitis) are urequent causes which is bilirubin glucuronide. An assay conducted in the ou predominantly conjugated hyperbilirubinemia. 324 SECTION VI Metabolism ou Proteins & Amino Acids Hyperbilirubinemia is usually modest (< 4 mg bilirubin per dL; tends not to exceed 20 mg/dL ow serum, and patients respond < 68 μmol/L) despite extensive hemolysis, due to the high to treatment with large doses ow phenobarbital. capacity ow a healthy liver to metabolize bilirubin. Toxic Hyperbilirubinemia DISORDERS OF BILIRUBIN Unconjugated hyperbilirubinemia can result wrom toxin- induced liver dysfunction caused by, wor example, chloro- METABOLISM worm, arsphenamines, carbon tetrachloride, acetaminophen, Neonatal “Physiologic Jaundice” hepatitis virus, cirrhosis, or Amanita mushroom poisoning. vhe unconjugated hyperbilirubinemia ow neonatal “physi- vhese acquired disorders involve hepatic parenchymal cell ologic jaundice” results wrom accelerated hemolysis and an damage, which impairs bilirubin conjugation. immature hepatic system wor the uptake, conjugation, and secretion ow bilirubin. In this transient condition, bilirubin- Obstruction in the Biliary Tree Is the glucuronosyltranswerase activity, and probably also synthesis Most Common Cause of Conjugated ow UDP-glucuronate, are reduced. When the plasma concen- Hyperbilirubinemia tration ow unconjugated bilirubin exceeds that which can be tightly bound by albumin (20–25 mg/dL), bilirubin can pen- Conjugated hyperbilirubinemia commonly results wrom etrate the blood–brain barrier. Iw lewt untreated, the resulting blockage ow the hepatic or common bile ducts, most owten hyperbilirubinemic toxic encephalopathy, or kernicterus, due to a gallstone or to cancer of the head of the pancreas can result in mental retardation. Exposure ow jaundiced neo- (Figure 31–14). Bilirubin diglucuronide that cannot be nates to blue light (phototherapy) promotes hepatic excretion excreted regurgitates into the hepatic veins and lymphatics, ow unconjugated bilirubin by converting some to derivatives conjugated bilirubin appears in the blood and urine (chol- that are excreted in the bile, and phenobarbital, a promoter ow uric jaundice), and the stools typically are a pale color. bilirubin metabolism, may be administered. vhe term cholestatic jaundice includes both all cases ow extrahepatic obstructive jaundice and also conjugated hyper- Defects of Bilirubin bilirubinemia due to micro-obstruction ow intrahepatic biliary ductules by damaged hepatocytes, such as may occur in inwec- UDP-Glucuronosyltransferase tious hepatitis. Glucuronosyltranswerases (EC 2.4.1.17), a wamily ow enzymes with diwwering substrate speciwicities, increase the polarity ow various drugs and drug metabolites, thereby wacilitating their PRE-HEPATIC Hemolytic anemias excretion. Mutations in the gene that encodes bilirubin UDP- (Vascular) glucuronosyltransferase can result in the encoded enzyme having reduced or absent activity. Syndromes whose clinical presentation rewlects the severity ow the impairment include Gilbert syndrome and two types ow Crigler-Najjar syndrome. HEPATIC Liver diseases (Liver) (eg, hepatitis, cancer) Gilbert Syndrome Providing that about 30% ow the bilirubin UDP-glucuronosyl- transwerase activity is retained in Gilbert syndrome, the condi- tion is harmless. Gallstone Type I Crigler-Najjar Syndrome POST-HEPATIC Pancreatic vhe severe congenital jaundice (over 20 mg bilirubin per dL (Biliary system & cancer serum) and accompanying brain damage ow type I Crigler- pancreas) Najjar syndrome rewlect the complete absence ow hepatic UDP-glucuronosyltranswerase activity. Phototherapy reduces plasma bilirubin levels somewhat, but phenobarbital has no benewicial ewwect. vhe disease is owten watal within the wirst 15 months ow liwe. FIGURE 31–14 Major causes of jaundice. Prehepatic jaun- dice indicates events in the bloodstream, major causes being various Type II Crigler-Najjar Syndrome hemolytic anemias. Hepatic jaundice arises urom hepatitis or other liver diseases (eg, cancer). Posthepatic jaundice reuers to events in In type II Crigler-Najjar syndrome, some bilirubin UDP- the biliary tree, uor which the major causes are obstruction ou the glucuronosyltranswerase activity is retained. vhis condition common bile duct by a gallstone (biliary calculus) or by cancer ou the thus is more benign than the type I syndrome. Serum bilirubin head ou the pancreas.  CHAPTER 31 Porphyrins & Bile Pigments 325 TABLE 31–4 Laboratory Results in Normal Patients and Patients With Three Different Causes of Jaundice Condition Serum Bilirubin Urine Urobilinogen Urine Bilirubin Fecal Urobilinogen Normal Direct: 0.1-0.4 mg/dL 0-4 mg/24 h Absent 40-280 mg/24 h Indirect: 0.2-0.7 mg/dL Hemolytic anemia ↑Indirect Increased Absent Increased Hepatitis ↑Direct and indirect Decreased iu micro-obstruction Present iu micro-obstruction Decreased is present occurs Obstructive jaundicea ↑Direct Absent Present Trace to absent a The most common causes ou obstructive (posthepatic) jaundice are cancer ou the head ou the pancreas and a gallstone lodged in the common bile duct. The presence ou bili- rubin in the urine is sometimes reuerred to as choluria—thereuore, hepatitis and obstruction ou the common bile duct cause choluric jaundice, whereas the jaundice ou hemolytic anemia is reuerred to as acholuric. The laboratory results in patients with hepatitis are variable, depending on the extent ou damage to parenchymal cells and the extent ou micro-obstruction to bile ductules. Serum levels ou alanine aminotransferase and aspartate aminotransferase are usually markedly elevated in hepatitis, whereas serum levels ou alkaline phosphatase are elevated in obstructive liver disease. Dubin-Johnson Syndrome ow prothrombin time) and on serum (eg, electrophoresis ow vhis benign autosomal recessive disorder consists ow conju- proteins; alkaline phosphatase and alanine aminotranswerase gated hyperbilirubinemia in childhood or during adult liwe. and aspartate aminotranswerase activities) also help to distin- vhe hyperbilirubinemia is caused by mutations in the gene guish between prehepatic, hepatic, and posthepatic causes ow encoding the protein involved in the secretion ow conjugated jaundice. bilirubin into bile. SUMMARY Some Conjugated Bilirubin Can Bind Te heme ow hemoproteins such as hemoglobin and the Covalently to Albumin cytochromes is an iron-porphyrin complex. Porphyrin consists ow wour pyrrole rings joined by methyne bridges. When levels ow conjugated bilirubin remain high in plasma, a Te eight methyl, vinyl, and propionyl substituents on the wour wraction can bind covalently to albumin. vhis wraction, termed pyrrole rings ow heme are arranged in a speciuc sequence. Te δ-bilirubin, has a longer half-life in plasma than does con- metal ion (Fe2+ in hemoglobin; Mg2+ in chlorophyll) is linked to ventional conjugated bilirubin, and remains elevated during the wour nitrogen atoms ow the pyrrole rings. recovery wrom obstructive jaundice. Some patients therewore Biosynthesis ow the heme ring involves eight enzyme-catalyzed continue to appear jaundiced even awter the circulating conju- reactions, some ow which occur in mitochondria, others in the gated bilirubin level has returned to normal. cytosol. Synthesis ow heme commences with the condensation ow Urinary Urobilinogen & Bilirubin Are succinyl-CoA and glycine to worm ALA. Tis reaction Clinical Indicators is catalyzed by ALAS1, the regulatory enzyme ow heme In complete obstruction of the bile duct, bilirubin has no biosynthesis. access to the intestine wor conversion to urobilinogen, so no Synthesis ow ALAS1 increases in response to a low level ow urobilinogen is present in the urine. vhe presence ow conju- available heme. For example, certain drugs (eg, phenobarbital) gated bilirubin in the urine without urobilinogen suggests indirectly trigger enhanced synthesis ow ALAS1 by promoting synthesis ow the heme protein cytochrome P450, which thereby intrahepatic or posthepatic obstructive jaundice. depletes the heme pool. By contrast, ALAS2 is not regulated In jaundice secondary to hemolysis, the increased pro- by heme levels, and consequently not by drugs that promote duction ow bilirubin leads to increased production ow urobilin- synthesis ow cytochrome P450. ogen, which appears in the urine in large amounts. Bilirubin Genetic abnormalities ow seven ow the eight enzymes ow heme is not usually wound in the urine in hemolytic jaundice, so biosynthesis result in inherited porphyrias. Erythrocytes the combination ow increased urobilinogen and absence ow and liver are the major sites ow expression ow the porphyrias. bilirubin is suggestive ow hemolytic jaundice. Increased blood Photosensitivity and neurologic problems are common destruction wrom any cause brings about an increase in urine complaints. Intake ow certain toxins (eg, lead) can cause urobilinogen. acquired porphyrias. Increased amounts ow porphyrins or their Table 31–4 summarizes laboratory results obtained in precursors can be detected in blood and urine, wacilitating patients with jaundice due to prehepatic, hepatic, or pos- diagnosis. thepatic causes: hemolytic anemia (prehepatic), hepatitis Catabolism ow the heme ring, initiated by the mitochondrial (hepatic), and obstruction of the common bile duct (posthe- enzyme heme oxygenase, produces the linear tetrapyrrole, patic); see Figure 31–14. Laboratory tests on blood (evalua- biliverdin. Subsequent reduction ow biliverdin in the cytosol h t t p s :// a l l e b o o k s t o r e s. c o m tion ow the possibility ow a hemolytic anemia and measurement worms bilirubin. 326 SECTION VI Metabolism ou Proteins & Amino Acids Bilirubin binds to albumin wor transport wrom peripheral Jaundice results wrom an elevated level ow plasma bilirubin. tissues to the liver, where it is taken up by hepatocytes. Te iron Te causes ow jaundice can be distinguished as prehepatic ow heme is released and reutilized. (eg, hemolytic anemias), hepatic (eg, hepatitis), or posthepatic Te water solubility ow bilirubin is increased by the addition (eg, obstruction ow the common bile duct). Measurements ow two moles ow the highly polar glucuronosyl moiety, derived ow plasma total and nonconjugated bilirubin, ow urinary wrom UDP-glucuronate, per mole ow bilirubin. Attachment urobilinogen and bilirubin, ow the activity ow certain serum ow the glucuronosyl moieties is catalyzed by bilirubin UDP- enzymes, and the analysis ow stool samples help distinguish glucuronosyltranswerase, one ow a large wamily ow enzymes ow between the causes ow jaundice. ditering substrate speciucities that increase the polarity ow various drugs and drug metabolites, thereby wacilitating their excretion. REFERENCES Mutations in the encoding gene may result in reduced or Ajioka RS, Phillips JD, Kushner JP: Biosynthesis ow heme in absent bilirubin UDP-glucuronosyltranswerase activity. Clinical mammals. Biochim Biophys Acta 2006;1763:723. presentations that refect the severity ow the mutation(s) include Desnick RJ, Astrin KH: Te porphyrias. In Harrison’s Principles Gilbert syndrome and two types ow Crigler-Najjar syndrome, of Internal Medicine, 17th ed. Fauci AS (editor). McGraw-Hill, conditions whose severity depend on the extent ow remaining 2008. glucuronosyltranswerase activity. Duwour DR: Liver disease. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 4th ed. Burtis CA, Ashwood ER, Following secretion ow bilirubin wrom the bile into the gut, Bruns DE (editors). Elsevier Saunders, 2006. bacterial enzymes convert bilirubin to urobilinogen and Higgins v, Beutler E, Doumas Bv: Hemoglobin, iron and urobilin, which are excreted in the weces and urine. bilirubin. In Tietz Textbook of Clinical Chemistry and Molecular Colorimetric measurement ow bilirubin employs the color Diagnostics, 4th ed. Burtis CA, Ashwood ER, Bruns DE (editors). wormed when bilirubin reacts with diazotized sulwanilic acid. Elsevier Saunders, 2006. Assays conducted in the absence ow added methanol measure Pratt DS, Kaplan MM: Evaluation ow liver wunction. In Harrison’s “direct bilirubin” (ie, bilirubin glucuronide). Assays conducted Principles of Internal Medicine, 17th ed. Fauci AS (editor). in the presence ow added methanol measure total bilirubin. Te McGraw-Hill, 2008. diterence between total bilirubin and direct bilirubin, termed Wolkot AW: Te hyperbilirubinemias. In Harrison’s Principles of “indirect bilirubin,” is unconjugated bilirubin. Internal Medicine, 17th ed. Fauci AS (editor). McGraw-Hill, 2008. Exam Questions Section VI - Metabolism of Proteins & Amino Acids 6. Select the one ow the wollowing statements that is NOv CORRECv: A. Angelman syndrome is associated with a dewective ubiquitin 1. Select the one ow the wollowing statements that is NOv E3 ligase. CORRECv: B. Following a protein-rich meal, the splanchnic tissues release A. Δ1-Pyrroline-5-carboxylate is an intermediate both in the predominantly branched-chain amino acids. which are biosynthesis and in the catabolism ow L-proline. taken up by peripheral muscle tissue. B. Human tissues can worm dietarily nonessential amino acids C. vhe rate ow hepatic gluconeogenesis wrom glutamine exceeds wrom amphibolic intermediates or wrom dietarily essential that ow any other amino acid. amino acids. D. vhe L-α-amino oxidase-catalyzed conversion ow an α-amino C. Human liver tissue can worm serine wrom the glycolytic acid to its corresponding α-keto acid is accompanied by the intermediate 3-phosphoglycerate. release ow NH4+. D. vhe reaction catalyzed by phenylalanine hydroxylase E. Similar or even identical signs and symptoms can be interconverts phenylalanine and tyrosine. associated with diwwerent mutations ow the gene that encodes E. vhe reducing power ow tetrahydrobiopterin derives a given enzyme. ultimately wrom NADPH. 7. Select the one ow the wollowing statements that is NOv CORRECv: 2. Identiwy the metabolite that does NOv serve as a precursor ow a A. PESv sequences target some proteins wor rapid degradation. dietarily essential amino acid: B. AvP and ubiquitin typically participate in the degradation A. α-Ketoglutarate ow membrane-associated proteins and other proteins with B. 3-Phosphoglycerate long halw-lives. C. Glutamate C. Ubiquitin molecules are attached to target proteins via D. Aspartate non-α peptide bonds. E. Histamine D. vhe discoverers ow ubiquitin-mediated protein degradation received a Nobel Prize. 3. Select the one ow the wollowing statements that is NOv E. Degradation ow ubiquitin-tagged proteins takes place in the CORRECv: proteasome, a multi-subunit macromolecule present in all A. Selenocysteine is present at the active sites ow certain human eukaryotes. enzymes. B. Selenocysteine is inserted into proteins by a 8. For metabolic disorders ow the urea cycle, which statement is posttranslational process. NOv CORRECv: C. vransamination ow dietary α-keto acids can replace the A. Ammonia intoxication is most severe when the metabolic dietary essential amino acids leucine, isoleucine, and valine. block in the urea cycle occurs prior to the reaction catalyzed D. Conversion ow peptidyl proline to peptidyl-4-hydroxyproline by argininosuccinate synthase. is accompanied by the incorporation ow oxygen into B. Clinical symptoms include mental retardation and the succinate. avoidance ow protein-rich woods. E. Serine and glycine are interconverted in a single reaction in C. Clinical signs can include acidosis. which tetrahydrowolate derivatives participate. D. Aspartate provides the second nitrogen ow argininosuccinate. 4. Select the CORRECv answer: E. Dietary management wocuses on a low-protein diet ingested vhe wirst reaction in the degradation ow most ow the protein amino as wrequent small meals. acids involves the participation ow: A. NAD+ 9. Select the one ow the wollowing statements that is NOv B. vhiamine pyrophosphate (vPP) CORRECv: C. Pyridoxal phosphate A. One metabolic wunction ow glutamine is to sequester D. FAD nitrogen in a nontoxic worm. E. NAD+ and vPP B. Liver glutamate dehydrogenase is allosterically inhibited by AvP and activated by ADP. 5. Identiwy the amino acid that is the major contributor to the C. Urea is wormed both wrom absorbed ammonia produced transport ow nitrogen destined wor excretion as urea: by enteric bacteria and wrom ammonia generated by tissue A. Alanine metabolic activity. B. Glutamine D. vhe concerted action ow glutamate dehydrogenase C. Glycine and glutamate aminotranswerase may be termed D. Lysine transdeamination. E. Ornithine E. Fumarate generated during biosynthesis ow argininosuccinate ultimately worms oxaloacetate in reactions h t t p s :// a l l e b o o k s t o r e s. c o m in mitochondria catalyzed successively by wumarase and malate dehydrogenase. 327 328 SECTION VI Metabolism ou Proteins & Amino Acids 10. Select the one ow the wollowing statements that is NOv 16. A 30-year-old man presented at clinic with a history ow CORRECv: intermittent abdominal pain and episodes ow conwusion and A. vhreonine provides the thioethanol moiety wor biosynthesis psychiatric problems. Laboratory tests revealed increases ow ow coenzyme A. urinary δ-aminolevulinate and porphobilinogen. Mutational B. Histamine arises by decarboxylation ow histidine. analysis revealed a mutation in the gene wor uroporphyrinogen I C. Ornithine serves as a precursor ow both spermine and synthase (porphobilinogen deaminase). vhe probable diagnosis spermidine. was: D. Serotonin and melatonin are metabolites ow tryptophan. A. Acute intermittent porphyria. E. Glycine, arginine, and methionine each contribute atoms wor B. X-linked sideroblastic anemia. biosynthesis ow creatine. C. Congenital erythropoietic porphyria. D. Porphyria cutanea tarda. 11. Select the one ow the wollowing statements that is NOv E. Variegate porphyria. CORRECv: A. Excreted creatinine is a wunction ow muscle mass, and can 17. Select the one ow the wollowing statements that is NOv be used to determine whether a patient has provided a CORRECv: complete 24-hour urine specimen. A. Bilirubin is a cyclic tetrapyrrole. B. Many drugs and drug catabolites are excreted in urine as B. Albumin-bound bilirubin is transported to the liver. glycine conjugates. C. High levels ow bilirubin can cause damage to the brains ow C. vhe major nonprotein metabolic wate ow methionine is newborn inwants. conversion to S-adenosylmethionine. D. Bilirubin contains methyl and vinyl groups. D. vhe concentration ow histamine in brain hypothalamus B. Bilirubin does not contain iron. exhibits a circadian rhythm. 18. A 62-year-old wemale presented at clinic with intense jaundice, E. Decarboxylation ow glutamine worms the inhibitory steadily increasing over the preceding 3 months. She gave a neurotransmitter GABA (γ-aminobutyrate). history ow severe upper abdominal pain. radiating to the back. 12. What distinguishes the routes by which each ow the wollowing and had lost considerable weight. She had noted that her stools amino acids appears in human proteins? had been very pale wor some time. Lab tests revealed a very high 5-Hydroxylysine level ow direct bilirubin. and also elevated urinary bilirubin. vhe γ-Carboxyglutamate plasma level ow alanine aminotranswerase (ALv) was only slightly Selenocysteine elevated, whereas the level ow alkaline phosphatase was markedly elevated. Abdominal ultrasonography revealed no evidence ow 13. What evolutionary advantage might be gained by the wact that gallstones. Ow the wollowing, which is the most likely diagnosis? certain amino acids are dietarily essential wor human subjects? A. Gilbert syndrome 14. What explanation can you owwer to explain that metabolic dewects B. Hemolytic anemia that result in the complete absence ow the activity ow glutamate C. vype 1 Crigler-Najjar syndrome dehydrogenase have not been detected? D. Carcinoma ow the pancreas E. Inwectious hepatitis 15. Which ow the wollowing is NOv a hemoprotein? 19. Clinical laboratories typically use diazotized sulwanilic acid to A. Myoglobin measure serum bilirubin and its derivatives. What is the physical B. Cytochrome c basis that permits the laboratory to report results to the physician C. Catalase in terms ow these two worms ow bilirubin? D. Cytochrome P450 E. Albumin 20. What signals the synthesis ow heme to take place?