648 • I'ARl IV METABOLlC l'ATHWAYSANU 'J'HEHH.

:O N lXU L

Oligo - or polysaccharides are linked to proteins via a limited • Generic disorders of glycosylation cause a wide range of pheno-
number of N- or 0-glycosyl bonds in glycoproreins and types , with examples from all clinical specialties. Many genetic
pro teoglycans. diseases o r complex carbohydrate metabolism result hom deti -
N-glycosylarion enrai~s a dolichol-linked assembly pathway and ciencies of glycosida.ses .
a mulri-comparm1enr ceUular processi ng pathway.
• Glycan structures modulate numerous molecular interactions
like cell signaling, aclliesion, and receptor activation.

16.1 • PFNTOSE PHOSPHATE PATHWAY

Pentose Phosphate Pathway Has Two Phases
The penrose phosphate pathway provides a means for degrading the carbon chain of a sugar
mnl<"c.ule. nne. c.~rhnn ~ r ::~ ri m<". Hnweve.r, rhis p~rhw:~y ~n~ nor c.nn.1rirnre. ::~ c.nns<"c.llriv<"
set of reactions that lead directly to C0 0 bur occurs in two phases. In th e first, hexose is
decarboxylated ro penrose via two oxidation reactions that form NADPH; in the second,
by a series of transformations, six molecules of penrose undergo rearrangements to yield five
molecules of hexose.

Glucose 6-Phosphate Oxidization Conserves Redox Equivalents

as NADPH and Decarboxylation Supplies Pentose Phosphates
The first reaction, catalyzed by glucose 6-phos phare (G6P) dehydrogenase (Figure 16.1) is
dehydrogenation of G6P ro form 6 -phosphoglucono-5-lactone and NADPH, and is a
major regulatory sire for this pathway. Special in terest in this enzyme stems from the ~evere
anemia that may result from absence of G6P dehydrogenase in erythrocytes or from t:he
presence of one of many generic variants of the enzyme (Ciin. Corr.l6.1). The lactone
product of this reaction is a substrate fo r gluconolacronase, wh ich ensures that t:he reactio n
go~ rn mmpleri nn. The. nve.r~ll e.'luilihri11m of hnrh rF~c.ri nn.< lie.s f::~r in th e. clirec.rinn of
NADPH, maintaining a high NADPH/NADP+ ratio within ~e.l!s. A second dehydrogena-
tion and decarboxylation, catalyzed by 6-phosphogluconate dehydrogenase, produces
the penrose phosphate, ribulose 5-phosphatc and a second molecule oiN/\DPH. Ribulose
5-phu.pbau:: i~ drm isomeri:tt:d lU rilm~ 5-phu,phate through au eneJiul imen aediatc:.

Glucose 6-Phosphate Dehydrogenase Deficiency

Glucose-6-phosph.ate dehydrogenase (G6PD) deficiency is the most can oxidi~e glucose ar a normal race when the demand for NADPH is
common human em yme defecr und may be present in as many as 4 00 normal. However, if the rare ofNADPH utilizarion is increased , the
million people worldwide. About 140 mutations have been described cells cannot mcrease d1e accivity of the parbway adequately. In add i-
in rhis protein of 5 1G amino acids, accounting for a wide range of tion, cells do nor reduct" enough NADP + ro maintain glutarhjon:
sympU>ms. The mun frc:yuem dinical rnan.ifc:statiom uf G6PD de- jn ir.s teuucc:J scare, a.rtu hence ro protecr against lipiu peruxiuaciun.
ficiency are neonatal jaundice and acute hemolytic anemia, which Reduced glutathione is necessary for the inregri ry of the erythrocyte
is usually triggered by an exogenous agem. When certain seemingly membrane, rhus rendering enzyme-deflcie:u red cells more suscep-
harmless drugs, such as antimalarials, antipyretics, or sulfa antibiotics, tible ro hemolysis by a wide range of compounds. This deficiency
are administered ro susceptible patiems, an acute hemolytic anemia illusuares the interplay of heredi ty and environmem in r:he produc-
may resulr [n 48- 96 h. Susceptibility co drug-induced hemolytic dis- tion of disease. Th~ most effective management of G6PD deficiency
ease is most o~ten due 10 a deficiency of glucose 6-phosphare (G6P) is ro prevenr hemolysis by avoiding oxidative scress. Complete defi-
dehydrogenase activi ty in erythrocytes, and was an early indicatio n ciency of GGPD is lerhal.
thar X-linked gene ric deficiencies of this enzyme exist. The enzyme
Lunarro, l., Mehta, .'\., and Vulliamy, T. Glucose G-phosphate dehydrogenase
is particularly important. si nce the penrose phosphate pathway is the deftden:y. In Scriver ,C. R., Beaude1, AR. , Sly, W. S.. and Valle, D. (Ed.~.). Thr
~jor ~rhway of NAOPH prnd ncrinn in rh<" r<"n rPII. Rr~ hlnnd ,~fctaboiic nnd Mokc"l" r B.TScs ofli•hcrircd Di.'<'ns<, Srh cd. New York: McGraw Hill,
cells with the relatively mild A-type G6P dehydrogenase deficiency 2001, Ill: 4517; :md G ppellini, M. D., :md Fiorelli, G .Lancer 371:64,2008.
 CHAI'I H 16 CA!{BOHY UIZA I EMETABOLISM JI :Sl' ECJALI'A I HWAYSAN U G LYCOCONJUGATES • 649
NADP' 1\ADPH + W
CHtJP0:~2-

\_)
~
HO I
I
HH H\ r
H OH
H
glucose
6-pnospnate
dGhydrogenase

Glucose
S·phosphate 5-Phosphoglucono-S-Iaetone

& phospho· f H20

guco·
tactonase
H+

0'\. p-
c
I
H - C - OH
I
HO - C - H
I
H - C - OH
I
H - C - OH
I
H - C - OPOi -
1
H

f
6.Phosphogluconate

6·phosphogluconate NADP+
rtP.hyrlroQAM SP.
NADPH - H+

C02
+
H
0'\. 1 H I
c H- <.; - UH
I I
H - C - OH C= O
I I
H - C - OH H- C - OH
I ribose 5· I
H - C - OH H- C - OH
phosphate
I isomerase I
H - C - OP032- H - C - OPO:J2-
I I
H H
Ribose S·phosphate Ribulose S·phosphate
Figure 16.1 Oxidative phase of the pentose p h osphate pathway: Formation of pentose phosphate
and NADPH.

Under cen ain metabolic conditions. the penrose phosphate pathway can end at this p oint.
with utilization of NADPH for red uctive bios;nthetic reactions and ribose )-phosphate as
a precu rsor fo r n ucleotide synth esis. The O\'e rall eq uation may be w rit ten as

Glucose 6-phos phate + 2NADP+ + H20 ~ ribose 5-phosp hare

+ 2NADPH + 2H + + C02

lnterconversions of Pentose Phosphates Lead

to Intermediates of Glycolysis
If more NAD PH is needed tor reductive b iosynthesis than ribose 5-phosphate tor incorpo·
ration into nucleorides, a sugar interconversion system (Figure 16.2) forms triose, tetrose,
hexo~e, and he ptose sugars from the penroses and provides a reversible link between the
650 • I'ARl IV METABOLlCl'ATHWAYSANU 'J'HEHH.:ONlXUL

H
I
H- C-OH
0 H I
"'c/ C=O
I I
11 - C - 011 HO-C - H
I 0 H I
H-C-OH '\ / H C OH
i;
I I I
II C Oil H -C-OH
H - c - oH
I I I
H-C-OPOj- H-C-OPO;i-
H - C - OPOa2-
1
phosphopentose /"
1
H
l H
H
H isomerase , /
I Ribose 5-phosphate Fructose 6-phosphate

,/
H - C - OH Glyceraldehyde 3-phosphate
trans aldolase
I +
C=O +
H
transketolase
0 H
H-C OH I H "'c/
H- C - OH
I ~ I I
H-C-OH ~ I H - C - OH H-C-OH
c- o I
I I
H - t - OP032- ' HO - C - H H-C -OH
I
H ph·~s~~O:!~~ose ~ 1-1
I
C Oil H-C -OPOj-
1
Ribulose 5-phosphate I H
H-c-opoj-
1
H Erythrose 4-phosphate

Xylulose 5-phosphate 1-1 - ~ - 01 1 (

II
H - ~ - opo 32- \ I
H-C-OH
I
Sedohept:lose 7-phosphate \L HO-::;- H
c-o
I
&foe - \ I
~\ H-C-OH
I
\~
H H-C-OP032-
I I
H-C - OH
H
I
C - 0
+ H- c - oH Xylulose 5-phosphate
I
HC - C - H I
I H- c - oPo32-
11- C - 011 l
H
H- C - OH
1 Olyceralclehyde 3-phosphate
11- C - OP0}-
1
H

Fructose 6-phosphate
Figure 16.2 Nonoxidative reactions of the pentose phosphate pathway: lnterconversions of
pentose phosphates.

penrme. phosph~re r~rhw~y ~ncl glyml)l'iS vi~ rommon i nte.rme.cli~rt'.~- Xylulo~e 5-pho~phate
is formed through isomerization of ribulose 5-phosphate by phosphopentose epimerase;
ribulose 5-phosphare, ribose 5-phosphare, and xylulose 5-phosphnre rhus exisr as an equilib-
rium mixture and can undergo transformations catalyzed by rranskcrolasc and transaldolasc.
Transkctolasc requires thiamin pyrophosphate (TPP) and diYalcnt cations, transfers
a c2 unit of actizle glycolaldehyde from xylulose 5-phosphate [0 ribose 5-phosphate, and
produces sedoheptulose and glyceraldehyde 3-phosphate, an intermediate of glycolysis.
Alrera!ions in transketolase can lead to Wernicke- Korsakoffsyndrome (Clin. Corr.l6.2).
Transaldolase rransfers a C3 unit (dihydroxyacetone) from sedoheptulose 7-phosphate to
glyceraldehyde 3-phosphate forming ery1hrose 4-pbosphate, and fructose 6-phosphate,
another intermediate of glycol)'sis. Transkerolase produces fructose 6-phosphate and
 CHAPTER IG CARBOHYDRATE METABOLISM II: SPECIAL PATHWAYS AND GLYCOCONJUGATES • 651

glyceraldehyde 3-phosphare, from eiythrose 4 -phosphare and xylulose 5-phosphare. The

sum of these reactions is
2 Xylulose 5-phosphare + ribose 5-phosphate ;;::::': 2 fructose 6-phosphare Wernicke-Korsakoff Syndrome
+ glyceraldehyde 3-phosphare (OMIM 277730): Associated
Since xylulose 5-phosphate is derived from ribose 5-phosphate, the net reaction starting
Anomalies in Transketolase
from ribose 5-phosphate is Activity
3 Ribose 5-phosphare ;;::::': 2 fructose 6-phosphare Symptoms of Wernicke- Korsakoff syn-
+ glyceraldehyde 3-phosphare drome become apparem afrer moderate
srress thar does nor affecr normal individu-
T hus, excess ribose 5-phosphate, produced in the first stage of the penrose phosphate pathway als, and an anomaly in rranskewlase has
or from degradation of nucleic acids, is effectively converted ro intermediates of glycolysis. been noted. Cloning and sequencing of
the transkerolase gene appears ro exclude
Glucose 6- Phosphate Can Be Completely Oxidized to C02 a generic defect. Rather, the dysfunction
of rranskerolase may be related ro a thia-
Complete oxidation of glucose 6- phosphate (G 6P) ro C02, with reduction of NADP + ro
min deficiency, since rranskerolase utilizes
NADPH, may also occur (Figure 16.3). G6P continually enters rhis pathway, and C02 and
thiamin pyrophosphate as a cofacror. The
NADPH are produced in the firsr phase. A balanced equarion includes the oxidation of six
syndrome presents as a mental disorder,
molecules of G6P ro six of ribulose 5-phosphare and six of C02. This resulrs in rransfer of
with memory loss and partial paralysis, and
12 pairs of electrons ro NADP+, the requisire amount for roral oxidation of one glucose ro
can become manifesr in alcoholics, whose
six C0 2. Six molecules of ribulose 5-phosphare are then reananged to generate five mol-
diers may be vitamin deficient. The medi-
ecules of G6P. T he overall equation then becomes
cal importance of rhe pentosc phosphate
6 G lucose 6-phosphare + 12NADP+ + ? H 20 ;;::::': 5 glucose 6-phosphate parhway is also highlighted by deficien-
+ 6C02 + 12NADPH + 12H+ + Pi cies in rransaldolase, which are linked to
a spectrum of clinical diseases, including
And the net reaction is
liver cirrhosis and male infertility.
Glucose 6-phosphate + 12NADP+ + ? H 20;;::::: 6C02 + 12N ADPH + 12H + + Pi
Perl, A. The pathology of transaldolase deficiency.
Lift 59:365, 2007
Pentose Phosphate Pathway Serves as a NADPH Regenerating
System and Supplier of Pentose Phosphates
T he penrose phosphate pathway serves several purposes, including synthesis and degradation
ofsugars other than hexoses, particularly ribose 5-phosphate for synthesis of nucleotides, and

ATP ADP (6) NADP+ (6) NADPH + (6) W H20

Glucose - '--
--"'--""'_.;(::__.._. (6) Glucose 6·phosphate '--- ..-! • 6-Phosphogluconolactone ___!"-----• 6·Phosphogluconate

(6) C02 + lr----- (6)NADP+

{6) NADPH + (6)W

(6) Ribulose 5-phosphate

(4) Xylulose 5-phosphate (2) Ribose 5-phosphate

(2) Fructose 6·phospnate

y
(2) Glyceraldehyde 3·phosphate + (2) Sedoheptulose 7·phosphate

y
+

Glyceraldehyde 3-phosphate

(2) Erythrose 4-phosphate + (2) Fructose 6-phosphate

Figure 16.3 Pentose phosphate pathway.

652 • I'ARl IV METABOLlCl'ATHWAYSANU 'J'HEHH.:ONlXUL

symhesis of NADPH. The proc~sing Aow of G6P after enrr; inro the pathway is determined
largely by the needs of the cell for NAlJl'H or sugar intermediates. When more NADl'H
than ribose 5-phosphate is required, the path leading m complete oxidation ot G6P to C02
and resynthesis of G6P from ribulose 5-phosphate is favored. Alternatively, if NADPH
demand is relatively low. conversion ofG6P ro ribulose 5-phosphate for nucleic acid synthe-
sis or recycling to produce intermediates of the glycolytic pathway predominates.
The tissue distriburion of the penrose phosphate pathway is consistent with its func-
rions. NADPH, required ro maintain reduced glutathione which prorects the integrity of red
hlnncl c.t>ll rnt>mhrmt>.~, i.1 prnclnc.e.cl in t>ryrhrnc.yrl":< , ~s we.ll ~~in liv~r. m::~mm~ry gbncl, rt>.~ri.1 ,
and adrenal correx, which are sires of fatty acid o r steroid synthesis. The balance between
glucose entry into g lycolysis or rhe penrose phosphate pathway depends on the metabolic
requirements of the organ. 20%- 30% of the C0 2 produced in the liver may arise irom the
pcntmc phosphate p athway. ln mammalian striated muscle, which c.urics on licclc faery acid
or steroid synthesis, all catabolism of G6P proceeds via gl)'colysis and the TCA cycle with no
direct oxidation of glucose 6 -phosphate through the penrose phosphate pathway.

16.2 • SUGAR INTERCONVERSIONS AND

NUCLEOTIDE-LINKED SUGAR FOJ&.1ATION
Most monosaccharides fou nd in biological compounds derive from glucose. The most
~liiJ UilUil su~ar lransfunnatiuns iu mammalian >plt:lll> arc swuu tarizeJ iu Figure 16.4.

Isomerization and Phosphorylation Are Common Reactions

for lnterconverting Carbohydrates
Formation of some sugars can occur directly, starting from g~ucose via modification reac-
tions such as the aldose-ketose isomerization catalyzed by phosphomannose isomerase,
which produces mannose 6 -phosphate. Deficiency in this enzyme leads to one torm ot
congenital disorders of glycos)'larion syndrome (CDGS) (p. 662).
Phosphotylation and internal transfer of a phosphate group on the same sugar molecule
are also common modifications. Glucose !-phosphate. resulting from glycogeno lysis, is con-
Yerted to G6P by pho.s phoglucomutase. Galactose is phosphorylated to galactose !-phosphate

Galactose Glucose Fructose Man nose

~ ATP f ATP +ATP ~ ATP
Galactose l ·P Glucose &P -:::;::=====~ Fructose 6-P Mamose 6·P
1~ l JTP nr lJOP·(IIum~P. ~· +glutamine
H
UDP-galaclose UDP-gluc~se -.------'~=-Glucose 1· P Glucosamine 6 -P Mamose 1·P
t N.'\0 LTP
+TIP
+
t GTP
JDP·glucuronic dTOP-glucose I\CAcetyi~IUCOS8mlne 6·1-' GDP·mannose
acid
f NADH ~t ~ NADH
t - C02 dTOP-rhamnose N-Acetylgalactosamine I·P GOP-fucose
UJP-xylose
t UTP
UD"-~acetylgalactosamine UDP· acet IQILcosamlne

N-AcetylmLnosamine

+ ATP
N-Acetylnannosamlne 6·1-'
phosphoenolp~ruvate +
N-Acetylneuraminic llCid 9-P

I - P;
GMP-N-acei)1Q_euraminlc acid ~ N-AcetylneJraminic acid
CTP
Figure 16.4 Pathways of formation of nucleotide-lin.k ed sugars and interconversion o1 some
hexoses.
 CHAI''lER 16 CARI30HYURA!EMElAI30LlSM ll: SI'EC lALI'A l HWAYSANUGLYCOCO NJUGATES • 653

Essential Fructosuria (OMIM 229800) and Fructose Intolerance (OMIM 229600):

Deficiency of Fructokinase and Fructose 1-Phosphate Aldolase
Frucmse may accounr for 30%-60% of me
roral carbohydrare in cake evenrual kidney failure. Ingeslion of frucrose or prolonged ingesrion
of mammals and is predominancly mcrabolized by a frucrose-specific by affecred young children may lead m dearh. Fructose 1-phosphare
p:~rhw:~y. Frurrnkin:t~<' i.~ d!'ficieor in fS~<'nri "' 1 frurrnsu ri"'. Thi.~ tii~nr­ :~ld nbs<' m:~y :~lso h<' rll'ficienr, in ,vhirh c.:ts<' f'rurrn.~r 1 -phn.~ph:tr<' :~c­
der is a benign asympromaric metabolic anomaly which appears robe cumulares inrracellularly (see C lin. Corr. 15.3, p. 607).
inherired as an autosomal recessive rroir. Following intake o f frucrose,
blood and urinary &ucrose levels of affected indiv iduals are unusually
Sreinmann, B., Gir:zelnunn, R., and Vanden Berghe, G. Disorders of frucrose
high; however, 90% of rhcir !"mcrosc in rake is cvcmually mcrabolizcd. merabolism.ln Scriver ,C. R., Beauder, A.R. , Sly, W. S., and Valle, D. (Eds.). Tbr
In ummtsL, hc:rcdirary fructose intolerance is chamcu::r i:.:eu uy se,err Mttnb?!ic aJtd M?leculm Bases of l11berited Dtsenst, 8th ed. New York: McGraw
hypoglycemia, jaundice, hemorrhage, heparomegaly, uricemia, and Hill, 2001 , 1:1489.

by galactokinase and mannose to mannose 6-phosphare by mannokinase. Free fructose. an

importam dietary constituent, is phosphorylared in rhe liver to fructose ! -phosphate by a special
frucrokinase. However, no mutase imerconvert.~ fructose ! -phos phate and fructose 6-phosphate,
and phosphofructokinase cannot symhesizefructose I ,6-bisphosphare from fructose 1- phmphace.
Rarhcr, fructose ! -phosphate aldolase cleaves frucrosc 1-phospharc ro dihydroxyacctonc
phosl'hate (DHAP), whidt ettleL~ the glycolytic pathway J irectly, a11U glyceraludtyJe, which
is firsr reduced ro glycerol, phosphorylated, and then reoxidized ro DrL<\P (Figure 15.39.
p. 625). Lack of this aldolase leads ro fructose intolerance (Ciin. ()}tT. 16.3).

Nucleotide-Linked Sugars Are Intermediates

in Many Sugar Transformations
Many sugar transformation reactions requ ire conversion inro nucleotide-linked sugars. A
pyrophosphorylase joins hexose ! -phosphate and nucleoside trip hosphate (NTP) to pro-
duce a nucleoside diphosphate (N D P> sugar and pyrophosphate. P yrophosphatase rapidly
hydrolyzes the pyrophosphate, thereby driving the synthesis reaction. These reactions are
summarized as follows :

NTP +sugar 1-p'losphate + H 20.,....:. NDP-sugar + PP;

l'l'; + H20 ~ 21';
The net reactio n is

NTP +sugar ! -phosphate+ H20 ~ N DP-sugar + 2P;

For example, UDP-glucose is used in synthesis of glycogen and glycoproreins and is
synthesized by UDP-glucose pyrophosphorylase.

Glucose

~~ o a
H~t_'o-f-o-f-o -Uridine + PP;
H OH o- o-
UOP-glucose
654 • I'ARl IV METABOLlCl'ATHWAYSANU 'J'HEHH.:ONlXUL

HOGH2 Nuc!eoside diphosphate-sugars are imporranr consa·ucrs: They comain rwo phosphoryl
HJ--=--0 bonds, each wirh a large negarive .l G ofhydrolys1s thar w1derlies their value as glycosyl donors
K~IHOO in further transformation and rranster reactions , and they conter substrate specificity in those
HO OH H 0-~-0-~-0-Uridine reactions. UOP is usually the glucosyl carrier, whereas ADP, GOP, and CMP are carriers for
I I other sugars. Many sugar rransformacion reactions occw· only ar rhe level of nucleotide-linked
H OH o- o-
UDP-glucose
sugars (Figure 16.4, p. 652).

I~ UDP-glucose-4-
Epimerization lnterconverts Nucleotide-Unked
~ I eplmerase Glucose and Galactose
lnrerconversion of glucose and galactose in animal cells occurs by epimerizacion of UDP-

00
HOGH2

H~:~
glucosc to UDP-galactosc, caralyzcd by U DP-glucosc-4-cpimcrasc (Figure. 16.5). UDI)-
galactosc: is also formed from free: galactose: , derived from h ydrolysis of !acrose in the:
H H
H OH
'o-~ -o- f-o-Uridine
o~ o-
inresrinal uacr. Galacrose is phosphorylated by galactokin ase and ATP 10 yield galacrose
1-phosphare. Then galactose !-phosph ate uridylyltransferase forms U DP-galacrose by
galacrose 1-phosphare displacing glucose !-phosphate from UDP-glucose. These reactions
UOP-Galactose
are swnmarized as foUows:
Figure 16.5 Conversion of glucose into
galactose. G alactose+ ATP ~ ga lactose ! -phosphate+ ADP

UDP-glucose + galactose ! -phosphate~ VOP-galactose + glucose l - phosphare

D ietary galacrose can be transformed by a combinarion of rhese reactions inro glucose
1-phosphare and merabolized as previously described, or the 4-epimerase can produce
UDP-galacrose needed for biosynthesis. A severe form of heredirary galacrosemia resulrs
G loco~e ti-om absence of the uridylyluansterase (Cl in. Corr. 16.4) .

~ Synthesis of GOP-fucose (see Figure. 16.4) begins w ith rhe conversion of GOP-man-
nose to GDP-4-kero-6 -deoxymannose by G DP-mannose-4,6-dehydratase, followed by
Glucose 6-phosp~ate
epimerizati on to G OP-4-kero-6 -deoxy-L-ga!actose, and finally reducrion to GO P-fucose.
~ These latrer reactions are catalyzed by the bifunctional GDP-4-ke to-6-d em:ym ann ose
Glucose 1-phosp1ate 3,5-epimerase-4-redu ctase (FX protein), which is abundant in red blood cells. Epimeriza-
~ tion of 0 -glucuronic acid to L- iduronic acid occurs afrer rhe former is incorporared into
heparin o r dermatan sulfate (p. 665).
UDP·Giucose

~ Glucuronic Acid Is Formed by Oxidation of UDP-Giucose

UDP-Giucurooic acid

~ The synrhesis of g lucuronic acid from glucose is summarized in Figure 16.6. A critical step is
D·Giucuronic acid 1·phosphate the oxidation ofUDP-glucosc by UDP-glu cosc d eh yd rogenase (Figure 16.7). Glucuronic

~ acid is reduced by N ADPH to L-gu lonic acid (f-igure 16.8) . G ulonic acid can be oxi-
dized w 3-kerogulonic acid and decarboxylared w L-xylulose. In humans , L-xylulose is the
o-Gucuronic add
Figure 16.6 Biosynthesis of D-glucuronic acid keropentose excrered in essential pentosuria (Ciin. Co rr. 16.5). L-Xylulose is normally
from glucose. reduced to xylitol, reoxidized ro D-xylulose and phosphorylated ro xylulose 5-phosphate,

Galactosemia: Inability to Transform Galactose into Glucose

Reactions of galacrose are of parricular inrerest because in humans they UDP galactose-4-epirnerase deficiency (Type 3, GALE gene) (OMIM
are subjccr to genericddecrs rhat produce rhe hereditary disorder galac- 230350). (;alactose is reduced ro galacrirol i:1 a reaction similar ro char
tosemia. When a defecr is presenr, individuals are unable to merabolize of glucose ro sorbirol. Galacrirol iniriates cararacr form arion in the lens
the galactose derived from lactose (milk sugar) to glucose metabolites, and may play a role in central nervous sysrem damage. Accurnularion of
ofren resulting in cararacr formation, growth failure, menral retarda- galacrose-1-phosphare is responsible for liver failure; rhe roxie effects of
tion, or evenrual dearh from ~ver damage. These phenorypes may be galacrosemetabolites disappear when galaerose is removed from the diet
due to a cellular deficiency of galacrokinase (Type 2, GALKI gene)
Petr)', K. G., and Reichardt, ]. K. The fundamental impona:-tce of human galactose.
(OMIM 230200). causing a relacively mild disorder characrerized by TrmdJ Genu. 14:98, 1998;Scriver. C. R., Beaudet, A. L, Valle, D., Sly, 'X'. S., Vofel-
<';l rly c-:tr:tr~ c-r tormarion; g:t bc-m~<' 1 -pho~ph:t r<' 11 ri.-lylylrr~n~tl'r<~~<' min, B., and Kinzl:r, K. W. Galactosemia Online Metabolic and Molecular Ba.<is of
(Type I, GALT gene) (OMIM 606999), resulting in severe disease; or Inherited Disea;e (hctp://www.onunbid.com/). New Yo~<: McGmw Hill, 2006.
 CHAI''II:J{ 16 CAR.BOHYUAAl'E ME"IABOLISM II: SPECIALPAl'HWAY:)ANU (.;LYU.JCO NJ UGAT ES • 655
HOCH2 H H
H 1--=-a\H I I
r~
HO\?H
l 0
7/ o-~-o-~-o-Uridine
0 H-RC-OH
H - C- OH
1\AD"II
H - C-OH
I
H-C - OH
H - C- OH
I
H - C- OH
' r-t'
H OH
I
o- o-
I I L·gulonic
HO-C-H
I I
C- H
HO-~=:JH
I t-oH
dehydrogenase
I
UDP·glucose H -C-OH H - C-OH
+ I I If
H C H-C-OH 0 C - OH
2 NAD+
I
I
c=o
'o-
C=O
' o-
L6=o
D·Giucuronlc acid L·Gulonlc acid L·Ascorbie acid
COOH
H 1--o\ H
rH ~/t'0-~-o-~-O-Uridine '~ 3·L-11ydroxy add dehyd rogenase

NAO•~~
0 0
HO\?i
I r---t I I
H OH o- a- "
UDP.glueuronle acid H H H
+ I I I
H-C - OH H-C-OH H - C-OH
2 NADH + 2 H+ I I -co2 I
NADPH
Figure 16.7 Formation of UOP-glucuronic acid H - C - OH H - C - OH H- C-OH
from UDP-glucose. I xylulose I j34<eto-L·gulonate
I
HO-C - H HO - C - H HO-C-H
rP.rtur.t~se rter.~rhoxyl ~sP.
I I I
H - C - OH r. =0 C= O
I I I
H - C - OH H - C - OH H- C - OH
I I I
H H c=o
' o-
Xylltol L·Xylulose 3·Kelogulonlc acid

H NAD+

H H
I I
H - C - OH H-c-oH
I I
c =0 C= O
I I
Ho - c - H HO - C-H
I ATP I
H - C - OH H-C-OH Pentose phosphate pathway
I xylu ose kinase I
H - C - OH H-C-OP032-
I I
H H

o-Xylulose Xylulose S·phosphate

Figure 16.8 Glucuronic acid oxidation pathway.

which can emer the penrose phosphate pathway described previously. Glucuronic acid is
also a precursor of L-ascorbic acid (Figure 16.8) in those animals that synthesize vitamin
C (Clin. Corr. 16.6) . Glucuronic acid also participates in deroxification by formation of
glucuronide conjugates (ClLn. Corr. 16.7). The glucumnic acid pathway operates in adi-
posf' ris.<I H~. ::~ncl ir~ ~criviry is mn::~l l y inrrf'::~se.cl in ri~siJP from .<rHvf'cl or cli ~ he.rir. :mim~ k

Decarboxylation, Oxidoreduction, and Transamidation

of Sugars Yield Necessary Products
The only known decarboxylation of a nucleotide-linked sugar is the conversion of UDP-
glucuronic acid to UDP->.-ylose, which is necessary for synthesis of proteoglycans (p. 664)
and is a potent inhibitor of the production of VUP-glucuronic acid by UUi'-glucose dehy·
drogenase (Figure 16.7), rhus regulating the level of these nucleotide-li nked sugar precur-
so rs by a sensitive feedback mechanism.