C H A P T E R

Catabolism of the Carbon

Skeletons of Amino Acids
Victor W. Rodwell, PhD
29
OBJ E C TI VE S ■ Name the principal catabolites of the carbon skeletons of the protein amino
acids and the major metabolic fates of these catabolites.
After studying this chapter, ■ Write an equation for an aminotransferase (transaminase) reaction and
you should be able to: illustrate the role played by the coenzyme.
■ Outline the metabolic pathways for each of the protein amino acids, and
identify reactions associated with clinically significant metabolic disorders.
■ Provide examples of aminoacidurias that arise from defects in glomerular
tubular reabsorption, and the consequences of impaired intestinal absorption
of tryptophan.
■ Explain why metabolic defects in different enzymes of the catabolism of a
specific amino acid can be associated with similar clinical signs and symptoms.
■ Describe the implications of a metabolic defect in Δ1-pyrroline-5-carboxylate
dehydrogenase for the catabolism of proline and of 4-hydroxyproline.
■ Explain how the α-amino nitrogen of proline and of lysine is removed by
processes other than transamination.
■ Draw analogies between the reactions that participate in the catabolism of
fatty acids and of the branched-chain amino acids.
■ Identify the specific metabolic defects in hypervalinemia, maple syrup urine
disease, intermittent branched-chain ketonuria, isovaleric acidemia, and
methylmalonic aciduria.

BIOMEDICAL IMPORTANCE of amino aids. The most reiae sreening tests use tandem
mass spetrometry to detet, in a few drops of neonate ood,
Chapter 28 desried the remova and the metaoi fate of ataoites suggestive of a given metaoi defet, and therey
the nitrogen atoms of most of the protein l-α-amino aids. impiate the asene or owered ativity of one or more spe-
This hapter addresses the metaoi fates of the resuting ifi enzymes.
hydroaron skeetons of eah of the protein amino aids, the Mutations either of a gene or of assoiated reguatory
enzymes and intermediates invoved, and severa assoiated regions of DNA an resut either in the faiure to synthesize
metaoi diseases or “inorn errors of metaoism.” Most the enoded enzyme, or in synthesis of a partiay or om-
disorders of amino aid ataoism are omparativey rare, petey nonfuntiona enzyme. Mutations that affet enzyme
ut if eft untreated, they an resut in irreversie rain dam- ativity, those that ompromise its three-dimensiona stru-
age and eary mortaity. Prenata or eary postnata detetion ture, or that disrupt its atayti or reguatory sites, an have
of metaoi disorders and timey initiation of treatment thus severe metaoi onsequenes. Low atayti effiieny of a
are essentia. The aiity to detet the ativities of enzymes in mutant enzyme an resut from impaired positioning of resi-
utured amnioti fuid es faiitates prenata diagnosis y dues invoved in ataysis, or in inding a sustrate, oenzyme,
amnioentesis. In the United States, a states ondut sreen- or meta ion. Mutations may aso impair the aiity of ertain
ing tests of neworns for up to 40 metaoi diseases, whih enzymes to respond appropriatey to the signas that moduate
inude disorders assoiated with defets in the ataoism

290
 CHAPTER 29 Catabolism of the Carbon Skeletons of Amino Acids 291

their ativity y atering an enzyme’s affinity for an aosteri TABLE 29–1 Fate of the Carbon Skeletons of the Protein
reguator of ativity. Sine different mutations an have simiar l-α-Amino Acids
effets on any of the aove fators, at a moeuar eve these rep- Converted to Amphibolic Intermediates That Form
resent distint moeuar diseases, athough various mutations
may give rise to the same inia signs and symptoms. Remedi- Glycogen and Fat
ation of metaoi disorders of amino aid metaoism onsists Carbohydrate Fat (Glycogenic and
(Glycogenic) (Ketogenic) Ketogenic)
primariy of feeding diets ow in the amino aid whose atao-
ism is impaired. Utimatey, however, geneti engineering may Ala Hyp Leu Ile
e ae to permanenty orret a given metaoi defet. Arg Met Lys Phe
Asp Pro Trp
AMINO ACIDS ARE CATABOLIZED Cys Ser Tyr
TO INTERMEDIATES FOR Glu Thr
CARBOHYDRATE & LIPID Gly Val
BIOSYNTHESIS His
Nutritiona studies in the period 1920 to 1940, reinfored and
onfirmed y studies using isotopiay aeed amino aids
onduted from 1940 to 1950, estaished the interonvertiiity
of the aron atoms of fat, arohydrate, and protein. These Asparagine & Aspartate Form
studies aso reveaed that a or a portion of the aron ske- Oxaloacetate
eton of every amino aid is onvertie either to arohydrate,
A four arons of asparagine and of aspartate form oxalo-
fat, or oth fat and arohydrate (Table 29–1). Figure 29–1
acetate via susequent reations atayzed y asparaginase
outines overa aspets of these interonversions.
(EC 3.5.1.1) and a transaminase.

TRANSAMINATION TYPICALLY Asparagine + H2O → Aspartate + NH+4

INITIATES AMINO ACID Aspartate + Pyruvate → Aanine + Oxaoaetate

CATABOLISM Glutamine & Glutamate Form

Remova of α-amino nitrogen y transamination, atayzed y
a transaminase (see Figure 28–9), is the first ataoi reation α-Ketoglutarate
of most of the protein amino aids. The exeptions are proine, Suessive reations atayzed y glutaminase (EC 3.5.1.2)
hydroxyproine, threonine, and ysine, whose α-amino groups and a transaminase form α-ketoglutarate.
do not partiipate in transamination. The hydroaron skee-
tons that remain are then degraded to amphioi intermediates Gutamine + H2O → Gutamate + NH+4
as outined in Figure 29–1. Gutamate + Pyruvate → Aanine + α-Ketogutarate

FIGURE 29–1 Overview of the amphibolic intermediates that result from catabolism of the protein amino acids.
292 SECTION VI Metabolism of Proteins & Amino Acids

Whie oth gutamate and aspartate are sustrates for the disorders of proine ataoism. Inherited as autosoma
same transaminase, metaoi defets in transaminases, whih reessive traits, oth are onsistent with a norma adut ife.
fufi entra amphioi funtions, may e inompatie with The metaoi ok in type I hyperprolinemia is at proline
ife. Consequenty, no known metaoi defet is assoiated dehydrogenase. There is no assoiated impairment of hydroxy-
with these two short ataoi pathways that onvert asparagine proine ataoism. The metaoi ok in type II hyperpro-
and gutamine to amphioi intermediates. linemia is at Δ1-pyrroine-5-aroxyate dehydrogenase, whih
aso partiipates in the ataoism of arginine, ornithine, and
Proline hydroxyproine (see ater). Sine proine and hydroxyproine
The ataoism of proine takes pae in mitohondria. Sine ataoism are affeted, oth Δ1-pyrroine-5-aroxyate and
proine does not partiipate in transamination, its α-amino Δ1-pyrroine-3-hydroxy-5-aroxyate (see Figure 29–11) are
nitrogen is retained throughout a two-stage oxidation to gu- exreted.
tamate. Oxidation to Δ1-pyrroine-5-aroxyate is atayzed
y proine dehydrogenase, EC 1.5.5.2. Susequent oxidation Arginine & Ornithine
to gutamate is atayzed y Δ1-pyrroine-5-aroxyate dehy- The initia reations in arginine ataoism are onversion to
drogenase (aso aed gutamate-γ-semiadehyde dehydro- ornithine foowed y transamination of ornithine to gutamate-γ-
genase, EC 1.2.1.88; Figure 29–2). There are two metaoi semiadehyde (Figure 29–3). Susequent ataoism of gutamate-
γ-semiadehyde to α-ketoglutarate ours as desried for proine
(see Figure 29–2). Mutations in ornithine δ-aminotransferase
(ornithine transaminase, EC 2.6.1.13) eevate pasma and uri-
nary ornithine, and are assoiated with gyrate atrophy of the
choroid and retina. Treatment invoves restriting dietary
arginine. In the hyperornithinemia–hyperammonemia syn-
drome, a defetive ORC1 mitohondria ornithine-citrulline
antiporter (see Figure 28–16) impairs transport of ornithine
into mitohondria, where it partiipates in urea synthesis.

Histidine
Cataoism of histidine proeeds via uroanate, 4-imidazoone-
5-propionate, and N-formiminogutamate (Figu). Formimino

FIGURE 29–3 Catabolism of arginine. Arginase-catalyzed

FIGURE 29–2 Catabolism of proline. Red bars and circled cleavage of l-arginine forms urea and l-ornithine. This reaction
numerals indicate the locus of the inherited metabolic defects in (red bar) represents the site of the inherited metabolic defect
1 type-I hyperprolinemia and 2 type-II hyperprolinemia. In this and in hyperargininemia. Subsequent transamination of ornithine
subsequent figures, blue highlights emphasize the portions of the to glutamate-γ-semialdehyde is followed by its oxidation to
molecules that are undergoing chemical change. α-ketoglutarate.
 CHAPTER 29 Catabolism of the Carbon Skeletons of Amino Acids 293

group transfer to tetrahydrofoate forms gutamate, then CATABOLISM OF GLYCINE,

α-ketoglutarate (Figure 29–4). In folic acid deficiency,
transfer of the formimino group is impaired, and Figu is SERINE, ALANINE,
exreted. Exretion of Figu foowing a dose of histidine thus CYSTEINE, THREONINE, &
an e used to detet foi aid defiieny. Benign disorders 4-HYDROXYPROLINE
of histidine ataoism inude histidinemia and urocanic
aciduria assoiated with impaired histidase and urocanase, Glycine
respetivey.
The glycine cleavage system of iver mitohondria spits gyine
to CO2 and NH+4 and forms N5,N10-methyene tetrahydrofoate.

Gyine + H4foate + NAD+ → CO2+ NH3 +

5,10-CH2-H4foate + NADH + H+

The gyine eavage ompex (Figure 29–5) onsists of three

enzymes and an “H-protein” that has a ovaenty attahed
dihydroipoy moiety. Figure 29–5 aso iustrates the individua
reations and intermediates in gyine eavage. In nonketotic
hyperglycinemia, a rare inorn error of gyine degradation,
gyine aumuates in a ody tissues inuding the entra
nervous system. The defet in primary hyperoxaluria is the
faiure to ataoize gyoxyate formed y the deamination of
gyine. Susequent oxidation of gyoxyate to oxaate resuts in
uroithiasis, nephroainosis, and eary mortaity from rena
faiure or hypertension. Glycinuria resuts from a defet in
rena tuuar reasorption.

Serine
Foowing onversion to gyine, atayzed y gyine hydroxy-
methytransferase (EC 2.1.2.1), serine ataoism merges with
that of gyine (Figure 29–6).

FIGURE 29–5 The glycine cleavage system of liver mitochon-

dria. The glycine cleavage complex consists of three enzymes and an
“H-protein” that has covalently attached dihyrolipoate. Catalysts for
FIGURE 29–4 Catabolism of l-histidine to α-ketoglutarate. the numbered reactions are 1 glycine dehydrogenase (decarbox-
(H4 folate, tetrahydrofolate.) The red bar indicates the site of an inher- ylating), 2 an ammonia-forming aminomethyltransferase, and 3
ited metabolic defect. dihydrolipoamide dehydrogenase. (H4 folate, tetrahydrofolate).
294 SECTION VI Metabolism of Proteins & Amino Acids

Methylene
H4 folate H4 folate
NH3+ NH3+

CH O– CH2 O–
H2C C C

HO O O
L-Serine Glycine

FIGURE 29–6 Interconversion of serine and glycine by gly-

cine hydroxymethyltransferase. (H4 folate, tetrahydrofolate.)

Alanine
Transamination of α-aanine forms pyruvate. Proay on
aount of its entra roe in metaoism, there is no known
viae metaoi defet of α-aanine ataoism.

Cystine & Cysteine

Cystine is first redued to ysteine y cystine reductase,
EC 1.8.1.6 (Figure 29–7). Two different pathways then on-
vert ysteine to pyruvate (Figure 29–8). There are numerous
anormaities of ysteine metaoism. Cystine, ysine, arginine,
and ornithine are exreted in cystine-lysinuria (cystinuria),
a defet in rena reasorption of these amino aids. Apart
from ystine aui, ystinuria is enign. The mixed disufide
of l-ysteine and l-homoysteine (Figure 29–9) exreted y
ystinuri patients is more soue than ystine and redues
formation of ystine aui.
Severa metaoi defets resut in vitamin B6-responsive
or vitamin B6-unresponsive homocystinurias. These inude a
defiieny in the reation atayzed y ystathionine β-synthase,
EC 4.2.1.22:
Serine + homoysteine → ystathionine + H2O

FIGURE 29–8 Two pathways catabolize cysteine: the cysteine

sulfinate pathway (top) and the 3-mercaptopyruvate pathway
(bottom).

CH2 S S CH2
+
H C NH3 CH2

COO –
H C NH3+

COO–
(Cysteine) (Homocysteine)

FIGURE 29–7 Reduction of cystine to cysteine by cystine FIGURE 29–9 Structure of the mixed disulfide of cysteine
reductase. and homocysteine.
 CHAPTER 29 Catabolism of the Carbon Skeletons of Amino Acids 295

Consequenes inude osteoporosis and menta retardation.

Defetive arrier-mediated transport of ystine resuts in cys-
tinosis (cystine storage disease) with deposition of ystine
rystas in tissues and eary mortaity from aute rena faiure.
Epidemioogi and other data ink pasma homoysteine eves
to ardiovasuar risk, ut the roe of homoysteine as a ausa
ardiovasuar risk fator remains ontroversia.

Threonine
Threonine adoase (EC 4.1.2.5) eaves threonine to gyine
and aetadehyde. Cataoism of gyine is disussed earier.
Oxidation of aetadehyde to aetate is foowed y formation
of aety-CoA (Figure 29–10).

4-Hydroxyproline
Cataoism of 4-hydroxy-l-proine forms, suessivey, l-Δ1-
pyrroine-3-hydroxy-5-aroxyate, γ-hydroxy-l-gutamate-γ-
semiadehyde, erythro-γ-hydroxy-l-gutamate, and α-keto-γ-
hydroxygutarate. An ado-type eavage then forms gyoxyate
pus pyruvate (Figure 29–11). A defet in4-hydroxyproline dehy-
drogenase resuts in hyperhydroxyprolinemia, whih is enign.
There is no assoiated impairment of proine ataoism. A defet

FIGURE 29–11 Intermediates in hydroxyproline catabolism.

(α-AA, α-amino acid; α-KA, α-keto acid.) Red bars indicate the sites of
FIGURE 29–10 Intermediates in the conversion of threonine the inherited metabolic defects in 1 hyperhydroxyprolinemia and
to glycine and acetyl-CoA. 2 type II hyperprolinemia.
296 SECTION VI Metabolism of Proteins & Amino Acids

in glutamate-γ-semialdehyde dehydrogenase is aompanied 3 to 4 days postpartum. Fase positives in premature infants

y exretion of Δ1-pyrroine-3-hydroxy-5-aroxyate. may refet deayed maturation of enzymes of phenyaanine
ataoism. An oder and ess reiae sreening test empoys
FeC3 to detet urinary phenypyruvate. FeC3 sreening for
ADDITIONAL AMINO ACIDS THAT PKU of the urine of neworn infants is ompusory in many
FORM ACETYL-CoA ountries, ut in the United States has een argey suppanted
y tandem mass spetrometry.
Tyrosine
Figure 29–12 iustrates the intermediates and enzymes that par- Lysine
tiipate in the ataoism of tyrosine to amphioi intermediates. Remova of the ε-nitrogen of ysine proeeds via initia for-
Foowing transamination of tyrosine to p-hydroxyphenypyruvate, mation of saccharopine and susequent reations that aso
suessive reations form homogentisate, maeyaetoaetate, ierate the α-nitrogen. The utimate produt of the aron
fumaryaetoaetate, fumarate, aetoaetate, and utimatey skeeton is rotony-CoA. Cired numeras refer to the or-
aety-CoA and aetate. responding numered reations of Figure 29–14. Reations 1
Severa metaoi disorders are assoiated with the tyrosine and 2 onvert the Shiff ase formed etween α-ketogutarate
ataoi pathway. The proae metaoi defet in type I tyro- and the ε-amino group of ysine to l-α-aminoadipate-δ-
sinemia (tyrosinosis) is at fumarylacetoacetate hydrolase, semiadehyde. Reations 1 and 2 oth are atayzed y a singe
EC 3.7.1.12 (reation 4, see Figure 29–12). Therapy empoys ifuntiona enzyme, aminoadipate-δ-semiadehyde synthase
a diet ow in tyrosine and phenyaanine. Untreated aute and (EC 1.5.1.8) whose N-termina andC-termina domains ontain
hroni tyrosinosis eads to death from iver faiure. Aternate ysine-α-ketogutarate redutase and saharopine dehydro-
metaoites of tyrosine are aso exreted in type II tyrosinemia genase ativity, respetivey. Redution of l-α-aminoadipate-
(Richner-Hanhart syndrome), a defet in tyrosine amino- δ-semiadehyde to l-α-aminoadipate (reation 3) is foowed
transferase (reation 1, see Figure 29–12), and in neonatal y transamination to α-ketoadipate (reation 4). Conversion
tyrosinemia, due to owered ativity of p-hydroxyphenypyruvate to the thioester gutary-CoA (reation 5) is foowed y the
hydroxyase, EC 1.13.11.27 (reation 2, see Figure 29–12). dearoxyation of gutary-CoA to rotony-CoA (reation 6).
Therapy empoys a diet ow in protein. Redution of rotony-CoA y rotanoy-CoA redutase,
The metaoi defet in alkaptonuria is a defetive homo- EC 1.3.1.86, forms utanoy-CoA:
gentisate oxidase (EC 1.13.11.5), whih atayzes reation 3 of
Figure 29–12. The urine darkens on exposure to air due to oxi- Crotony-CoA + NADPH + H+- → utanoy-CoA + NADP+
dation of exreted homogentisate. Late in the disease, there is
arthritis and onnetive tissue pigmentation (ohronosis) due Susequent reations are those of fatty aid ataoism
to oxidation of homogentisate to enzoquinone aetate, whih (see Chapter 22).
poymerizes and inds to onnetive tissue. First desried Hyperysinemia an resut from a metaoi defet in
in the 16th entury ased on the oservation that the urine either the first or seond ativity of the ifuntiona enzyme
darkened on exposure to air, akaptonuria provided the asis aminoadipate-δ-semiadehyde synthase, ut ony if the defet
for Sir Arhiad Garrod’s eary 20th entury assi ideas on- invoves the seond ativity that is aompanied y eevated
erning heritae metaoi disorders. Based on the presene eves of ood saharopine. A metaoi defet at reation 6
of ohronosis and on hemia evidene, the eariest known resuts in an inherited metaoi disease that is assoiated
ase of akaptonuria is, however, its detetion in 1977 in an with striata and ortia degeneration, and is haraterized y
Egyptian mummy dating from 1500 b.c.! eevated onentrations of gutarate and its metaoites guta-
onate and 3-hydroxygutarate. The haenge in inia man-
Phenylalanine agement of these metaoi defets is to restrit dietary intake
of l-ysine without produing manutrition.
Phenyaanine is first onverted to tyrosine (see Figure 27–12).
Susequent reations are those of tyrosine (see Figure 29–12).
Hyperphenylalaninemias arise from defets in phenyaanine Tryptophan
hydroxyase, EC 1.14.16.1 (type I, classic phenylketonuria Tryptophan is degraded to amphioi intermediates via the
[PKU], frequeny 1 in 10,000 irths), in dihydroiopterin kynurenine-anthraniate pathway (Figure 29–15). Tryptophan
redutase (types II and III), or in dihydroiopterin iosyn- 2,3-dioxygenase, EC 1.13.11.11 (tryptophan pyrrolase)
thesis (types IV and V) (see Figure 27–12). Aternative ata- opens the indoe ring, inorporates moeuar oxygen, and
oites are exreted (Figure 29–13). A diet ow in phenyaanine forms N-formykynurenine. Tryptophan oxygenase, an iron
an prevent the menta retardation of PKU. porphyrin metaoprotein that is induie in iver y adre-
DNA proes faiitate prenata diagnosis of defets in na ortiosteroids and y tryptophan, is feedak inhiited
phenyaanine hydroxyase or dihydroiopterin redutase. y niotini aid derivatives, inuding NADPH. Hydroyti
Eevated ood phenyaanine may not e detetae unti remova of the formy group of N-formykynurenine, atayzed
 FIGURE 29–12 Intermediates in tyrosine catabolism. Carbons are numbered to emphasize their ultimate fate. (α-KG, α-ketoglutarate; Glu, glutamate; PLP, pyridoxal phosphate.)
Red bars indicate the probable sites of the inherited metabolic defects in type II tyrosinemia; neonatal tyrosinemia; 1 alkaptonuria; and 2 type I tyrosinemia, or tyrosinosis. 3 alkapton-
uria; and 4 type I tyrosinemia, or tyrosinosis.
297
298 SECTION VI Metabolism of Proteins & Amino Acids

FIGURE 29–14 Reactions and intermediates in the catabolism

of lysine.

THE INITIAL REACTIONS ARE

COMMON TO ALL THREE
FIGURE 29–13 Alternative pathways of phenylalanine BRANCHED-CHAIN AMINO ACIDS
catabolism in phenylketonuria. The reactions also occur in normal Severa of the initia reations of the ataoism of isoeuine,
liver tissue but are of minor significance. euine, and vaine (Figure 29–19) are anaogous to reations
of fatty aid ataoism (see Figure 22–3). Foowing transami-
y kynurenine formylase (EC 3.5.1.9), produes kynurenine. nation (see Figure 29–19, reation 1), the aron skeetons of
Sine kynureninase (EC 3.7.1.3) requires pyridoxa phos- the resuting α-keto aids undergo oxidative dearoxyation
phate, exretion of xanthurenate (Figure 29–16) in response to and onversion to oenzyme A thioesters. This mutistep
a tryptophan oad is diagnosti of vitamin B6 defiieny. proess is atayzed y the mitochondrial branched-chain
Hartnup disease refets impaired intestina and rena trans- α-ketoacid dehydrogenase complex, whose omponents are
port of tryptophan and other neutra amino aids. Indoe funtionay identia to those of the pyruvate dehydrogenase
derivatives of unasored tryptophan formed y intestina ompex (PDH) (see Figure 18–5). Like PDH, the ranhed-
ateria are exreted. The defet imits tryptophan avaiaiity hain α-ketoaid dehydrogenase ompex onsists of five
for niain iosynthesis and aounts for the peagra-ike signs omponents.
and symptoms.
E1: thiamin pyrophosphate (TPP)-dependent ranhed-
hain α-ketoaid dearoxyase
Methionine E2: dihydroipoy transayase (ontains ipoamide)
Methionine reats with ATP forming S-adenosymethionine,
E3: dihydroipoamide dehydrogenase (ontains FAD)
“ative methionine” (Figure 29–17). Susequent reations
form propiony-CoA (Figure 29–18), whose onversion to PDH ompex kinase (PDK)
suiny-CoA ours via reations 2, 3, and 4 of Figure 19–2. PDH ompex phosphatase (PDP)
 FIGURE 29–15 Reactions and intermediates in the catabolism of tryptophan. (PLP, pyridoxal phosphate.)
299
300 SECTION VI Metabolism of Proteins & Amino Acids

O
METABOLIC DISORDERS OF
C BRANCHED-CHAIN AMINO ACID
CH2
CATABOLISM
CH O– As the name impies, the odor of urine in maple syrup urine
N N C
H2 H3+ disease (branched-chain ketonuria, or MSUD) suggests mape
HO O syrup, or urnt sugar. The iohemia defet in MSUD invoves
3-Hydroxykynurenine the α-ketoacid decarboxylase complex(reation 2, Figure 29–19).
Pasma and urinary eves of euine, isoeuine, vaine, and their
ognate α-keto aids and α-hydroxy aids (redued α-keto aids)
NH4+ are eevated, ut the urinary keto aids derive prinipay from
euine. Signs and symptoms of MSUD often inude ketoaidosis,
OH neuroogi derangements, menta retardation, and a mape syrup
odor of urine. The mehanism of toxiity is unknown. Eary
diagnosis y enzymati anaysis is essentia to avoid rain
damage and eary mortaity y repaing dietary protein y an
O–
C
amino aid mixture that aks euine, isoeuine, and vaine.
N
The moeuar genetis of MSUD are heterogeneous.
HO O MSUD an resut from mutations in the genes that enode E1α,
Xanthurenate E1β, E2, and E3. Based on the ous affeted, geneti sutypes of
MSUD are reognized. Type IA MSUD arises from mutations in
FIGURE 29–16 Formation of xanthurenate in vitamin B6 defi- the E1α gene, type IB in the E1β gene, type II in the E2 gene, and
ciency. Conversion of the tryptophan metabolite 3-hydroxykynurenine type III in the E3 gene (Table 29–2). In intermittent branched-
to 3-hydroxyanthranilate is impaired (see Figure 29–15). A large portion
is therefore converted to xanthurenate. chain ketonuria, the α-ketoaid dearoxyase retains some
ativity, and symptoms our ater in ife. In isovaleric acidemia,
ingestion of protein-rih foods eevates isovaerate, the deaya-
tion produt of isovaery-CoA. The impaired enzyme in iso-
As for pyruvate dehydrogenase (see Figure 17–6), the valeric acidemia is isovaleryl-CoA dehydrogenase, EC 1.3.8.4
PDH ompex kinase and PDH ompex phosphatase regu- (reation 3, Figure 29–19). Vomiting, aidosis, and oma fo-
ate ativity of the ranhed-hain α-ketoaid dehydrogenase ow ingestion of exess protein. Aumuated isovaery-CoA is
ompex via phosphoryation (inativation) and dephosphor- hydroyzed to isovaerate and exreted.
yation (ativation). Table 29–3 summarizes the metaoi disorders assoi-
Dehydrogenation of the resuting oenzyme A thioesters ated with the ataoism of amino aids, and ists the impaired
(reation 3, Figure 29–19) proeeds ike the dehydrogenation enzyme, its IUB enzyme ataog (EC) numer, a ross-referene
of ipid-derived fatty ay-CoA thioesters (see Chapter 22). to a speifi figure, and numered reation in this text, and a
Figures 29–20, 29–21, and 29–22 iustrate the susequent numeria ink to the Onine Mendeian Inheritane in Man
reations unique for eah amino aid skeeton. (OMIM) dataase.

COO– COO–
+ +
H3N C H H3N C H

CH2 CH2
P P P H2O Pi + PPi
CH2 CH2

S + CH2 +S
Adenine CH2 Adenine
O O
CH3 L-Methionine CH3
Ribose adenosyltransferase Ribose

HO OH HO OH
L-Methionine ATP S-Adenosyl-L-methionine
(“active methionine”)

FIGURE 29–17 Formation of S-adenosylmethionine. ~ CH3 represents the high group transfer potential of “active methionine.”
 CHAPTER 29 Catabolism of the Carbon Skeletons of Amino Acids 301

FIGURE 29–18 Conversion of methionine to propionyl-CoA.

302 SECTION VI Metabolism of Proteins & Amino Acids

FIGURE 29–19 The first three reactions in the catabolism of leucine, valine, and isoleucine. Note the analogy of reactions 2 and 3 to
reactions of the catabolism of fatty acids (see Figure 22–3). The analogy to fatty acid catabolism continues, as shown in subsequent figures.

FIGURE 29–20 Catabolism of the β-methylcrotonyl-CoA formed from l-leucine. Asterisks indicate carbon atoms derived from CO2.
 CHAPTER 29 Catabolism of the Carbon Skeletons of Amino Acids 303

FIGURE 29–21 Subsequent catabolism of the tiglyl-CoA

formed from l-isoleucine.

TABLE 29–2 Maple Syrup Urine Disease Can Reflect

Impaired Function of Various Components of the
α-Ketoacid Decarboxylase Complex
Maple
Branched-Chain α-Ketoacid OMIMa Syrup Urine
FIGURE 29–22 Subsequent catabolism of the methacrylyl-
CoA formed from l-valine (see Figure 29–19). (α-AA, α-amino acid;
Decarboxylase Component Reference Disease
α-KA, α-keto acid.)
E1α α-Ketoacid decarboxylase 608348 Type 1A
E1β α-Ketoacid decarboxylase 248611 Type 1B
E2 Dihydrolipoyl transacylase 608770 Type II
E3 Dihydrolipoamide 238331 Type III
dehydrogenase

a
Online Mendelian Inheritance in Man database: ncbi.nlm.nih.gov/omim/.
304 SECTION VI Metabolism of Proteins & Amino Acids

TABLE 29–3 Metabolic Diseases of Amino Acid Metabolism

Enzyme Catalog Figure and
Defective Enzyme Number OMIMa Reference Major Signs and Symptoms Reaction

S-Adenosylhomocysteine hydrolase 3.3.1.1 180960 Hypermethioninemia 29–18➂

Arginase 3.5.3.1 207800 Argininemia 29–3➀
Cystathionine-β-synthase 4.2.1.22 236200 Homocystinuria 29–18➃
Fumarylacetoacetate hydrolase 3.7.1.12 276700 Type I tyrosinemia (tyrosinosis) 29–12➃
Histidine ammonia lyase (histidase) 4.3.1.3 609457 Histidinemia & urocanic acidemia 29–4➀
Homogentisate oxidase 1.13.11.5 607474 Alkaptonuria. Homogentisate excreted 29–12➂
p-Hydroxyphenylpyruvate hydroxylase 1.13.11.27 276710 Neonatal tyrosinemia 29–12➂
Isovaleryl-CoA dehydrogenase 1.3.8.4 607036 Isovaleric acidemia 29–19➂
Branched chain α-ketoacid 248600 Branched-chain ketonuria (MSUD) 29–19➀
decarboxylase complex
Methionine adenosyltransferase 2.5.1.6 250850 Hypermethioninemia 29–17➀
Ornithine-δ-aminotransferase 2.6.1.13 258870 Ornithemia, gyrate atrophy 29–3➁
Phenylalanine hydroxylase 1.14.16.1 261600 Type I (classic) phenylketonuria 27–9➀
Proline dehydrogenase 1.5.5.2 606810 Type I hyperprolinemia 29–2➀

Δ’-Pyrroline-5-carboxylate 1.2.1.88 606811 Type II hyperprolinemia & hyper 29–2➁

dehydrogenase 4-hydroxyprolinemia
Saccharopine dehydrogenase 1.5.1.7 268700 Saccharopinuria 29–14➁
Tyrosine aminotransferase 2.6.1.5 613018 Type II tyrosinemia 29–12➀

a
Online Mendelian Inheritance in Man database: ncbi.nlm.nih.gov/omim/.

ataoism inude periodi and persistent forms of

SUMMARY hyperysinemia-ammonemia.
■ Exess amino aids are ataoized to amphioi intermediates
■ The ataoism of euine, vaine, and isoeuine presents
that serve as soures of energy or for the iosynthesis of
many anaogies to fatty aid ataoism. Metaoi disorders of
arohydrates and ipids.
ranhed-hain amino aid ataoism inude hypervainemia,
■ Transamination is the most ommon initia reation of amino mape syrup urine disease, intermittent ranhed-hain
aid ataoism. Susequent reations remove any additiona ketonuria, isovaeri aidemia, and methymaoni aiduria.
nitrogen and restruture hydroaron skeetons for onversion
to oxaoaetate, α-ketogutarate, pyruvate, and aety-CoA.
■ Metaoi diseases assoiated with gyine ataoism inude REFERENCES
gyinuria and primary hyperoxauria. Biksrud YT, Brodtkor E, Andresen PA, et a: Tyrosinemia type I,
■ Two distint pathways onvert ysteine to pyruvate. Metaoi de novo mutation in iver tissue suppressing an inorn spiing
disorders of ysteine ataoism inude ystine-ysinuria, defet. J Mo Med 2005;83:406.
ystine storage disease, and the homoystinurias. Dorowoski SF, Pey AL, Koh R, et a: Biohemia haraterization
■ Threonine ataoism merges with that of gyine after threonine of mutant phenyaanine hydroxyase enzymes and orreation
adoase eaves threonine to gyine and aetadehyde. with inia presentation in hyperphenyaaninaemi patients.
J Inherit Meta Dis 2009;32:10.
■ Foowing transamination, the aron skeeton of tyrosine is
Garg U, Dasouki M: Expanded neworn sreening of inherited
degraded to fumarate and aetoaetate. Metaoi diseases
metaoi disorders y tandem mass spetrometry. Cinia and
of tyrosine ataoism inude tyrosinosis, Rihner-Hanhart
aoratory aspets. Cin Biohem 2006;39:315.
syndrome, neonata tyrosinemia, and akaptonuria.
Geng J, Liu A: Heme-dependent dioxygenases in tryptophan
■ Metaoi disorders of phenyaanine ataoism inude PKU oxidation. Arh Biohem Biophys 2014;44:18.
and severa hyperphenyaaninemias. Hedt K, Shwahn B, Marquardt I, et a: Diagnosis of mape syrup
■ Neither nitrogen of ysine partiipates in transamination. urine disease y neworn sreening aows eary intervention
The same net effet is, however, ahieved y the intermediate without extraneous detoxifiation. Mo Genet Meta
formation of saharopine. Metaoi diseases of ysine 2005;84:313.