Harper's Biochemistry Chapter 30 - Conversion of Amino Acids to Specialized Products PDF

C H A P T E R Conversion of Amino Acids to Specialized Products Victor W. Rodwell, PhD 30 OBJ EC T IVES Cite examples of how amino acids participate in a va...

C H A P T E R Conversion of Amino Acids to Specialized Products Victor W. Rodwell, PhD 30 OBJ EC T IVES Cite examples of how amino acids participate in a variety of biosynthetic processes other than protein synthesis. After studying this chapter, Outline how arginine participates in the biosynthesis of creatine, nitric oxide you should be able to: (NO), putrescine, spermine, and spermidine. Indicate the contribution of cysteine and of β-alanine to the structure of coenzyme A. Discuss the role played by glycine in drug catabolism and excretion. Document the role of glycine in the biosynthesis of heme, purines, creatine, and sarcosine. Identify the reaction that converts an amino acid to the neurotransmitter histamine. Document the role of S-adenosylmethionine in metabolism. Recognize the structures of tryptophan metabolites serotonin, melatonin, tryptamine, and indole 3-acetate. Describe how tyrosine gives rise to norepinephrine and epinephrine. Illustrate the key roles of peptidyl serine, threonine, and tyrosine in metabolic regulation and signal transduction pathways. Diagram the roles of glycine, arginine, and S-adenosylmethionine in the biosynthesis of creatine. Explain the role of creatine phosphate in energy homeostasis. Illustrate the formation of γ-aminobutyrate (GABA) and the rare metabolic disorders associated with defects in GABA catabolism. BIOMEDICAL IMPORTANCE aergic reactions. Neurotransmitters derived rom amino acids incude γ-aminobutyrate (GABA), 5-hydroxytryptamine Certain proteins contain amino acids that have been post- (serotonin), dopamine, norepinephrine, and epinephrine. transationay modiied to permit them to perorm speciic Many drugs used to treat neuroogic and psychiatric condi- unctions. Exampes incude the carboxyation o gutamate to tions act by atering the metaboism o these neurotransmitters. orm γ-carboxygutamate, which unctions in Ca2+ binding, the Discussed beow are the metaboism and metaboic roes o hydroxyation o proine to orm 3- and 4-hydroxyproine in seected α- and non–α-amino acids. coagen, and the hydroxyation o ysine to 5-hydroxyysine, whose subsequent modiication and cross-inking stabiize maturing coagen ibers. In addition to serving as the buid- l-α-AMINO ACIDS ing bocks or protein synthesis, amino acids serve as precur- sors o bioogic materias as diverse and important as heme, Alanine purines, pyrimidines, hormones, neurotransmitters, and bio- Aanine serves as a carrier o ammonia and o the carbons ogicay active peptides. Histamine pays a centra roe in many o pyruvate rom skeeta musce to iver via the Cori cyce 306  CHAPTER 30 Conversion of Amino Acids to Specialized Products 307 FIGURE 30–1 Arginine, ornithine, and proline metabolism. Reactions with solid arrows all occur in mammalian tissues. Putrescine and spermine synthesis occurs in both mammals and bacteria. Arginine phosphate of invertebrate muscle functions as a phosphagen analogous to creatine phosphate of mammalian muscle. (see Chapters 19 & 28), and together with gycine constitutes a major raction o the ree amino acids in pasma. Arginine Figure 30–1 summarizes the metaboic ates o arginine. In addition to serving as a carrier o nitrogen atoms in urea bio- synthesis (see Figure 28–16), the guanidino group o argi- nine is incorporated into creatine, and oowing conversion to ornithine, its carbon skeeton serves as a precursor o the poyamines putrescine and spermine (see beow). he reaction catayzed by nitric oxide synthase, EC 1.14.13.39 (Figure 30–2), a ive-eectron oxidoreductase with mutipe coactors, converts one nitrogen o the guanidine group o arginine to nitric oxide, an interceuar signaing moecue that serves as a neurotransmitter, smooth musce reaxant, and vasodiator (see Chapter 51). Cysteine Cysteine participates in the biosynthesis o coenzyme A (see Chapter 44) by reacting with pantothenate to orm 4-phosphopantothenoycysteine. In addition, taurine, ormed rom cystreine, can dispace the coenzyme A moiety o choy- CoA to orm the bie acid taurochoic acid (see Chapter 26). he conversion o cysteine to taurine invoves cataysis by the nonheme Fe2+ enzyme cysteine dioxygenase (EC 1.13.11.20), suinoaanine decarboxyase (EC 4.1.1.29), and hypotaurine dehydrogenase (EC 1.8.1.3) (Figure 30–3). Arginine Citrulline + NO 2 O2 3/2 NADPH + H+ 3/2 NADP+ FIGURE 30–3 Conversion of cysteine to taurine. The reac- tions are catalyzed by cysteine dioxygenase, cysteine sulfinate decar- FIGURE 30–2 The reaction catalyzed by nitric oxide synthase. boxylase, and hypotaurine decarboxylase, respectively. 308 SECTION VI Metabolism of Proteins & Amino Acids O SH + C N (CH3)3 O– N NH2+ CH O– CH2 C Benzoate O ATP CoASH Ergothioneine AMP + PPi O CH2 NH3+ C CH2 O NH N NH2+ C S CoA CH O– CH2 C O Benzoyl-CoA Carnosine Glycine O CH2 NH3+ CoASH C CH2 + CH3 N N NH O H CH O– C CH2 O– CH2 C N C H O O Anserine Hippurate FIGURE 30–4 Biosynthesis of hippurate. Analogous reactions O CH2 CH2 occur with many acidic drugs and catabolites. C CH2 NH3+ NH N NH2+ Glycine CH O– CH2 C Many reativey apoar metaboites are converted to water-sou- be gycine conjugates. An exampe is the hippuric acid ormed O rom the ood additive benzoate (Figure 30–4). Many drugs, Homocarnosine drug metaboites, and other compounds with carboxy groups aso are conjugated with gycine. his makes them more water FIGURE 30–6 Derivatives of histidine. Colored boxes sur- soube and thereby aciitates their excretion in the urine. round the components not derived from histidine. The SH group of ergothioneine derives from cysteine. Gycine is a component o creatine, and its nitrogen and α-carbon are incorporated into the pyrroe rings and the meth- yene bridge carbons o heme (see Chapter 31). he entire gy- Histidine-containing compounds present in the human body cine moecue suppies atoms 4, 5, and 7 o the purine bases incude carnosine, and dietariy derived ergothioneine and (see Figure 33–1). anserine (Figure 30–6). Carnosine (β-aany-histidine) and homocarnosine (γ-aminobutyry-histidine) are major constit- Histidine uents o excitabe tissues, brain, and skeeta musce. Urinary eves o 3-methyhistidine are unusuay ow in patients with Decarboxyation o histidine to histamine is catayzed by the Wilson disease. pyridoxa 5′-phosphate-dependent enzyme histidine decar- boxyase, EC 4.1.1.22 (Figure 30–5). A biogenic amine that unctions in aergic reactions and gastric secretion, hista- Methionine mine is present in a tissues. Its concentration in the brain he major nonprotein ate o methionine is conversion hypothaamus varies in accordance with a circadian rhythm. to S-adenosymethionine, the principa source o methy groups in the body. Biosynthesis o S-adenosymethionine rom methionine and AP is catayzed by methionine ade- nosytranserase (MA), EC 2.5.1.6 (Figure 30–7). Human tissues contain three MA isozymes: MA-1 and MA-3 o iver and MA-2 o nonhepatic tissues. Athough hyper- methioninemia can resut rom severey decreased hepatic FIGURE 30–5 The reaction catalyzed by histidine MA-1 and MA-3 activity, i there is residua MA-1 or decarboxylase. MA-3 activity and MA-2 activity is norma, a high tissue  CHAPTER 30 Conversion of Amino Acids to Specialized Products 309 Methionine + Mg-ATP + H2O concentration o methionine wi ensure synthesis o adequate amounts o S-adenosymethionine. Foowing decarboxyation o S-adenosymethionine by Mg-PPi + Pi methionine decarboxyase (EC 4.1.1.57), three carbons and CH3 the α-amino group o methionine can be utiized or the Adenine biosynthesis o the poyamines spermine and spermidine. + S H3N + O hese poyamines unction in ce proieration and growth, COO– are growth actors or cutured mammaian ces, and stabiize intact ces, subceuar organees, and membranes. Pharma- coogic doses o poyamines are hypothermic and hypotensive. OH OH Since they bear mutipe positive charges, poyamines readiy S-Adenosylmethionine associate with DNA and RNA. Figure 30–8 summarizes the FIGURE 30–7 Biosynthesis of S-adenosylmethionine, cata- biosynthesis o poyamines rom methionine and ornithine, lyzed by methionine adenosyltransferase. and Figure 30–9 the cataboism o poyamines. Methionine + Mg-ATP + H2O COO– + Mg-PPi + Pi H3N NH3+ CH3 Adenine L-Ornithine + S H3N + O Ornithine COO– decarboxylase CO2 OH OH S-Adenosylmethionine + H3N CO2 NH3+ S-Adenosylmethionine Putrescine decarboxylase CH3 Adenine + S H3N + O OH OH Decarboxylated S-adenosylmethionine Spermidine synthase CH3 Adenine S + O OH OH Methylthio- adenosine + H3N NH3+ Spermidine Decarboxylated S-adenosylmethionine Spermine synthase Methylthio- adenosine + H3N NH3+ Spermine FIGURE 30–8 Intermediates and enzymes that participate in the biosynthesis of spermidine and spermine. 310 SECTION VI Metabolism of Proteins & Amino Acids oxidase, EC 1.4.3.4 (Figure 30–10). he psychic stimuation that oows administration o iproniazid resuts rom its abiity to proong the action o serotonin by inhibiting monoamine oxidase. In carcinoid (argentainoma), tumor ces overpro- duce serotonin. Urinary metaboites o serotonin in patients with carcinoid incude N-acetyserotonin gucuronide and the gycine conjugate o 5-hydroxyindoeacetate. Serotonin and 5-methoxytryptamine are metaboized to the correspond- ing acids by monoamine oxidase. N-Acetyation o serotonin, oowed by its O-methyation in the pinea body, orms mea- tonin. Circuating meatonin is taken up by a tissues, incud- ing brain, but is rapidy metaboized by hydroxyation oowed by conjugation with suate or with gucuronic acid. Kidney tissue, iver tissue, and eca bacteria a convert tryptophan to tryptamine, then to indoe 3-acetate. he principa norma uri- nary cataboites o tryptophan are 5-hydroxyindoeacetate and indoe 3-acetate (Figure 30–10). Tyrosine Neura ces convert tyrosine to epinephrine and norepi- nephrine (Figure 30–11). Whie dopa is aso an intermediate in the ormation o meanin, dierent enzymes hydroxyate tyrosine in meanocytes. DOPA decarboxyase (EC 4.1.1.28), a pyridoxa phosphate-dependent enzyme, orms dopamine. Subsequent hydroxyation, catayzed by dopamine β-oxidase (EC 1.14.17.1), then orms norepinephrine. In the adrena medua, phenyethanoamine N-methytranserase (EC 2.1.1.28) utiizes S-adenosymethionine to methyate the primary amine o norepinephrine, orming epinephrine (Figure 30–11). yro- sine is aso a precursor o triiodothyronine and thyroxine (see FIGURE 30–9 Catabolism of polyamines. Chapter 41). Phosphoserine, Phosphothreonine, & Serine Phosphotyrosine Serine participates in the biosynthesis o sphingosine (see Chapter 24), and o purines and pyrimidines, where it pro- he phosphoryation and dephosphoryation o speciic sery, vides carbons 2 and 8 o purines and the methy group o threony, or tyrosy residues o proteins reguate the activity o thymine (see Chapter 33). Genetic deects in cystathionine certain enzymes o ipid and carbohydrate metaboism and o β-synthase (EC 4.2.1.22) proteins that participate in signa transduction cascades (see Chapter 42). Serine + Homocysteine → Cystathionine + H2O a heme protein that catayzes the pyridoxa 5′-phosphate– Sarcosine (N-Methylglycine) dependent condensation o serine with homocysteine to orm he biosynthesis and cataboism o sarcosine (N-methygycine) cystathionine, resut in homocystinuria. Finay, serine (not occur in mitochondria. Formation o sarcosine rom dimethy cysteine) serves as the precursor o peptidy seenocysteine gycine is catayzed by the avoprotein dimethy gycine dehy- (see Chapter 27). drogenase EC 1.5.8.4, which requires reduced pteroypenta- gutamate (PG). Tryptophan Dimethygycine + FADH2 + H4PG + H2O → Sarcosine Foowing hydroxyation o tryptophan to 5-hydroxytryptophan + N-ormy-PG by iver tryptophan hydroxyase (EC 1.14.16.4), subsequent races o sarcosine can aso arise by methyation o gycine, a decarboxyation orms serotonin (5-hydroxytryptamine), a reaction catayzed by gycine N-methytranserase, EC 2.1.1.20. potent vasoconstrictor and stimuator o smooth musce con- traction. Cataboism o serotonin is initiated by deamination to Gycine + S-Adenosymethionine → Sarcosine 5-hydroxyindoe-3-acetate, a reaction catayzed by monoamine + S-Adenosyhomocysteine  CHAPTER 30 Conversion of Amino Acids to Specialized Products 311 HO CH2 NH3+ CH COO– N H 5-Hydroxytryptophan CO2 HO CH2 NH3+ CH2 N O2 H 5-Hydroxytryptamine (serotonin) CH3 MAO Acetyl-CoA [NH4+] HO CH2 O– O CH2 NH3+ C H3C CH2 O N CoASH N H H 5-Hydroxyindole- 5-Methoxytryptamine Excreted as 3-acetate conjugates H HO CH2 N CH3 CH2 C O2 O CH3 N MAO H [NH4+] N-Acetylserotonin O CH2 O– O CH2 O– H3C C H3C C O CH3 O N N H H 5-Methoxyindole- 5-Methoxyindole- 3-acetate 3-acetate H O CH2 N CH3 H2C CH2 C O N H Excreted as Melatonin Excreted as conjugates (N-acetyl-5-methoxyserotonin) conjugates FIGURE 30–10 Biosynthesis and metabolism of serotonin and melatonin. ([NH4+], by transamination; MAO, monoamine oxidase; ~CH3, from S-adenosylmethionine.) Cataboism o sarcosine to gycine, catayzed by the avopro- Creatine & Creatinine tein sarcosine dehydrogenase EC 1.5.8.3, aso requires reduced Creatinine is ormed in musce rom creatine phosphate by PG. irreversibe, nonenzymatic dehydration, and oss o phosphate Sarcosine + FAD + H4PG + H2O → Gycine + FADH2 (Figure 30–12). Since the 24-hour urinary excretion o creati- + N-ormy-PG nine is proportionate to musce mass, it provides a measure o whether a compete 24-hour urine specimen has been coected. he demethyation reactions that orm and degrade sarcosine Gycine, arginine, and methionine a participate in creatine represent important sources o one-carbon units. FADH2 is biosynthesis. Synthesis o creatine is competed by methyation reoxidized via the eectron transport chain (see Chapter 13). o guanidoacetate by S-adenosymethionine (Figure 30–12). 312 SECTION VI Metabolism of Proteins & Amino Acids FIGURE 30–12 Biosynthesis of creatine and creatinine. Conversion of glycine and the guanidine group of arginine to creatine FIGURE 30–11 Conversion of tyrosine to epinephrine and and creatine phosphate. Also shown is the nonenzymic hydrolysis of norepinephrine in neuronal and adrenal cells. (PLP, pyridoxal creatine phosphate to creatinine. phosphate.) hydroysis o β-aany dipeptides by the enzyme carnosinase, NON–α-AMINO ACIDS EC 3.4.13.20. β-Aminoisobutyrate aso arises by transamina- Non–α-amino acids present in tissues in a ree orm incude tion o methymaonate semiadehyde, a cataboite o l-vaine β-aanine, β-aminoisobutyrate, and GABA. β-Aanine is aso (see Figure 29–22). present in combined orm in coenzyme A, and in the β-aany he initia reaction o β-aanine cataboism is transami- dipeptides carnosine, anserine, and homocarnosine (see beow). nation to maonate semiadehyde. Subsequent transer o coenzyme A rom succiny-CoA orms maony-CoA semia- dehyde, which is then oxidized to maony-CoA and decarbox- β-Alanine & β-Aminoisobutyrate yated to the amphiboic intermediate acety-CoA. Anaogous β-Aanine and β-aminoisobutyrate are ormed during catab- reactions characterize the cataboism o β-aminoisobutyrate. oism o the pyrimidines uraci and thymine, respectivey ransamination orms methymaonate semiadehyde, which (see Figure 33–9). races o β-aanine aso resut rom the is converted to the amphiboic intermediate succiny-CoA by  CHAPTER 30 Conversion of Amino Acids to Specialized Products 313 FIGURE 30–13 Metabolism of γ-aminobutyrate. (α-AA, α-amino acids; α-KA, α-keto acids; PLP, pyridoxal phosphate.) reactions 8V and 9V o Figure 29–22. Disorders o β-aanine γ-Aminobutyrate and β-aminoisobutyrate metaboism arise rom deects in GABA unctions in brain tissue as an inhibitory neurotrans- enzymes o the pyrimidine cataboic pathway. Principa among mitter by atering transmembrane potentia dierences. GABA these are disorders that resut rom a tota or partia deiciency is ormed by decarboxyation o gutamate by l-gutamate o dihydropyrimidine dehydrogenase (see Chapter 33). decarboxyase, EC 4.1.1.15 (Figure 30–13). ransamination o GABA orms succinate semiadehyde, which can be reduced to β-Alanyl Dipeptides γ-hydroxybutyrate by l-actate dehydrogenase, or be oxidized he β-aany dipeptides carnosine and anserine (N-methy- to succinate and thence via the citric acid cyce to CO2 and H2O carnosine) (Figure 30–6) activate myosin APase (EC 3.6.4.1), (Figure 30–13). A rare genetic disorder o GABA metaboism cheate copper, and enhance copper uptake. β-Aany-imidazoe invoves a deective GABA aminotranserase EC 2.6.1.19, an buers the pH o anaerobicay contracting skeeta musce. enzyme that participates in the cataboism o GABA subse- Biosynthesis o carnosine is catayzed by carnosine synthetase quent to its postsynaptic reease in brain tissue. Deects in suc- (EC 6.3.2.11) in a two-stage reaction that invoves initia or- cinic semiadehyde dehydrogenase, EC 1.2.1.24 (Figure 30–13) mation o an enzyme-bound acy-adenyate o β-aanine and are responsibe or 4-hydroxybutyric aciduria, a rare meta- subsequent transer o the β-aany moiety to l-histidine. boic disorder o GABA cataboism characterized by the pres- ence o 4-hydroxybutyrate in urine, pasma, and cerebrospina AP + β-Aanine → β-Aany-AMP + PPi uid (CSF). No present treatment is avaiabe or the accompa- β-Aany-AMP + l-Histidine → Carnosine + AMP nying mid-to-severe neuroogic symptoms. Hydroysis o carnosine to β-aanine and l-histidine is catayzed by carnosinase. he heritabe disorder carnosinase deiciency is characterized by carnosinuria. SUMMARY Homocarnosine (Figure 30–6, present in human brain at In addition to serving structura and unctiona roes in higher eves than carnosine, is synthesized in brain tissue by proteins, α-amino acids participate in a wide variety o other carnosine synthetase. Serum carnosinase does not hydroyze biosynthetic processes. homocarnosine. Homocarnosinosis, a rare genetic disorder, Arginine provides the ormamidine group o creatine and the is associated with progressive spastic parapegia and menta nitrogen o NO. Via ornithine, arginine provides the skeeton retardation. o the poyamines putrescine, spermine, and spermidine. 314 SECTION VI Metabolism of Proteins & Amino Acids Cysteine provides the thioethanoamine portion o coenzyme and β-aminoisobutyrate metaboism arise rom deects in A, and oowing its conversion to taurine, is part o the bie enzymes o pyrimidine cataboism. acid taurochoic acid. Decarboxyation o gutamate orms the inhibitory Gycine participates in the biosynthesis o heme, purines, neurotransmitter GABA. wo rare metaboic disorders are creatine, and N-methygycine (sarcosine). Many drugs and associated with deects in GABA cataboism. drug metaboites are excreted as gycine conjugates. Tis enhances their water soubiity or urinary excretion. Decarboxyation o histidine orms the neurotransmitter REFERENCES histamine. 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Kidney and iver tissue, and aso eca bacteria, convert Jansen EE, Voge KR, Saomons GS, et a: Correation o bood tryptophan to tryptamine and thence to indoe 3-acetate. Te biomarkers with age inorms pathomechanisms in succinic principa tryptophan cataboites in urine are indoe 3-acetate semiadehyde dehydrogenase deciency (SSADHD), a disorder and 5-hydroxyindoeacetate. o GABA metaboism. J Inherit Metab Dis 2016;39:795. yrosine orms norepinephrine and epinephrine, and oowing Manegod C, Homann GF, Degen I, et a: Aromatic L-amino acid iodination the thyroid hormones triiodothyronine and decarboxyase deciency: cinica eatures, drug therapy and thyroxine. oowup. J Inherit Metab Dis 2009;32:371. Moinard C, Cynober L, de Bandt JP: Poyamines: metaboism and Te enzyme-catayzed interconversion o the phospho- and impications in human diseases. Cin Nutr 2005;24:184. dephospho- orms o peptide-bound serine, threonine, and Montioi R, Dindo M, Giorgetti A, et a: A comprehensive tyrosine pays key roes in metaboic reguation, incuding picture o the mutations associated with aromatic amino acid signa transduction. decarboxyase deciency: rom moecuar mechanisms to Gycine, arginine, and S-adenosymethionine a participate in therapy impications. Hum Mo Genet 2014;23:5429. the biosynthesis o creatine, which as creatine phosphate serves Pear PL, Gibson KM, Cortez MA, et a: Succinic semiadehyde as a major energy reserve in musce and brain tissue. Excretion dehydrogenase deciency: essons rom mice and men. J Inherit in the urine o its cataboite creatinine is proportionate to Metab Dis 2009;32:343. musce mass. Schippers KJ, Nichos SA: Deep, dark secrets o meatonin in anima β-Aanine and β-aminoisobutyrate both are present in tissues evoution. Ce 2014;159:9. as ree amino acids. β-Aanine aso occurs in bound orm Werni C, Finochiaro S, Voken C, et a: argeted screening o in coenzyme A. Cataboism o β-aanine invoves stepwise succinic semiadehyde dehydrogenase deciency (SSADHD) conversion to acety-CoA. Anaogous reactions cataboize empoying an enzymatic assay or γ-hydroxybutyric acid (GHB) β-aminoisobutyrate to succiny-CoA. Disorders o β-aanine in biofuids. Mo Genet Metab Rep. 2016;17:81.  C H A P T E R Porphyrins & Bile Pigments Victor W. Rodwell, PhD O B J E C TI V E S 31 Write the structural ormulas o the two amphibolic intermediates whose condensation initiates heme biosynthesis. After studying this chapter, Identiy the enzyme that catalyzes the key regulated step o hepatic heme you should be able to: biosynthesis. Explain why, although porphyrinogens and porphyrins both are tetrapyrroles, porphyrins are colored whereas porphyrinogens are colorless. Speciy the intracellular locations o the enzymes and metabolites o heme biosynthesis. Outline the causes and clinical presentations o various porphyrias. Identiy the roles o heme oxygenase and o UDP-glucosyl transerase in heme catabolism. Defne jaundice, name some o its causes, and suggest how to determine its biochemical basis. Speciy the biochemical basis o the clinical laboratory terms “direct bilirubin” and “indirect bilirubin.” BIOMEDICAL IMPORTANCE pyrrole rings. Examples include iron porphyrins such as the heme o hemoglobin and the magnesium-containing porphy- he biochemistry o the porphyrins and o the bile pig- rin chlorophyll, the photosynthetic pigment o plants. Heme ments are closely related topics. Heme is synthesized rom proteins are ubiquitous in biology and serve diverse unctions porphyrins and iron, and the products o degradation o including, but not limited to, oxygen transport and storage heme include the bile pigments and iron. he biochemistry o (eg, hemoglobin and myoglobin) and electron transport (eg, the porphyrins and o heme is basic to understanding the cytochrome c and cytochrome P450). Hemes are tetrapyr- varied unctions o hemoproteins, and the porphyrias, roles, o which two types, heme b and heme c, predominate a group o diseases caused by abnormalities in the pathway (Figure 31–2). In heme c the vinyl groups o heme b are o porphyrin biosynthesis. A much more common clinical replaced by covalent thioether links to an apoprotein, typically condition is jaundice, a consequence o an elevated level o via cysteinyl residues. Unlike heme b, heme c thus does not plasma bilirubin, due either to overproduction o bilirubin readily dissociate rom its apoprotein. or to ailure o its excretion. Jaundice occurs in numerous Proteins that contain heme are widely distributed in nature diseases ranging rom hemolytic anemias to viral hepatitis (Table 31–1). Vertebrate heme proteins generally bind one and to cancer o the pancreas. mole o heme c per mole, although those o nonvertebrates may bind signiicantly more heme. PORPHYRINS Porphyrins are cyclic compounds ormed by the linkage HEME IS SYNTHESIZED FROM o our pyrrole rings through methyne (—— HC—) bridges (Figure 31–1). Various side chains can replace the eight SUCCINYL-CoA & GLYCINE numbered hydrogen atoms o the pyrrole rings. he biosynthesis o heme involves both cytosolic and mito- Porphyrins can orm complexes with metal ions that orm chondrial reactions and intermediates. Heme biosynthesis coordinate bonds to the nitrogen atom o each o the our occurs in most mammalian cells except mature erythrocytes, 315