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The International Journal of Biochemistry & Cell Biology 45 (2013) 2563– 2567

Contents lists available at ScienceDirect

The International Journal of Biochemistry& Cell Biology

journa l h om epage: www.elsev ier .com/ locate /b ioce l

olecules in focus

icarbonyl/l-xylulose reductase (DCXR): The multifunctionalentosuria enzyme

un-Kyung Leea,b,c,∗, Le Tho Sond, Hee-Jung Choie, Joohong Ahnna,b,c,∗∗

Department of Life Science, Hanyang University, Seoul 133-791, Republic of KoreaThe Research Institute of Natural Sciences, Hanyang University, Seoul 133-791, Republic of KoreaBK21 PLUS Life Science for BDR Team, Hanyang University, Seoul 133-791, Republic of KoreaBiodiversity Research Center, Academia Sinica (BRCAS), Taipei, TaiwanSchool of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea

r t i c l e i n f o

rticle history:eceived 12 July 2013ccepted 15 August 2013vailable online 27 August 2013

eywords:icarbonyl/l-xylulose dehydrogenase

a b s t r a c t

Dicarbonyl/l-xylulose reductase (DCXR) is a highly conserved and phylogenetically widespread enzymeconverting l-xylulose into xylitol. It also reduces highly reactive �-dicarbonyl compounds, thus per-forming a dual role in carbohydrate metabolism and detoxification. Enzymatic properties of DCXR fromyeast, fungi and mammalian tissue extracts are extensively studied. Deficiency of the DCXR gene causesa human clinical condition called pentosuria and low DCXR activity is implicated in age-related diseasesincluding cancers, diabetes, and human male infertility. While mice provide a model to study clinical

hs-21entosuriaongevityertility

condition of these diseases, it is necessary to adopt a physiologically tractable model in which geneticmanipulations can be readily achieved to allow the fast genetic analysis of an enzyme with multiplebiological roles. Caenorhabditis elegans has been successfully utilized as a model to study DCXR. Here, wediscuss the biochemical properties and significance of DCXR activity in various human diseases, and theutility of C. elegans as a research platform to investigate the molecular and cellular mechanism of theDCXR biology.

. Introduction

DCXR (EC 1.1.1.10) is an evolutionarily conserved metabolicnzyme to reduce l-xylulose to xylitol (Fig. 1). In some fungind yeasts, DCXR functions in the oxy-reductive l-arabinose path-ay that catabolizes l-arabinose, which is an abundant pentose in

iomass (Fonseca et al., 2007). In higher organisms, DCXR func-ions in the glucuronate pathway, that is an alternate pathway oflucose-6-phosphate oxidation, which accounts for up to 5% of theotal glucose catabolism in humans (Fig. 2) (Kaneko et al., 1997).

�-Dicarbonyl compounds (DCs) are routinely generated in the

ourse of various normal metabolic reactions (Busch et al., 2010).Cs are widely reactive and tend to convert into advanced glyca-

ion end-products (AGEs), that are frequently accumulated in the

Abbreviations: DCXR, dicarbonyl/l-xylulose reductase; SDR, short-chain dehy-rogenase/reductase; DC, �-dicarbonyl compound; AGE, advanced glycationnd-products; DEP, diesel exhaust particles; RAGE, receptor for AGE.∗ Corresponding author at: Department of Life Science, Hanyang University, Seoul

33-791, Republic of Korea. Tel.: +82 222204484.∗∗ Corresponding author at: Department of Life Science, Hanyang University, Seoul33-791, Republic of Korea. Tel.: +82 222204474

E-mail addresses: sunkyungl@hanyang.ac.kr,unkyunglee3@gmail.com (S.-K. Lee), joohong@hanyang.ac.kr (J. Ahnn).

357-2725/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.biocel.2013.08.010

© 2013 Elsevier Ltd. All rights reserved.

plasma proteins and tissues of diabetics, associated with kidneyfailure, and advanced aging. DCXR efficiently reduces DCs to detox-ify endogenous and xenobiotic carbonyl compounds (Nakagawaet al., 2002). DCXR has been implicated in many human clinical dis-orders. Deficiency of DCXR causes pentosuria, a historically famousinborn metabolic disease (Scriver, 2008). DCXR is suggested as abiomarker in cancer, and also to be critical for human sperm mat-uration and fertility (Cho-Vega et al., 2007a; Sullivan, 2004).

Caenorhabditis elegans, a free-living soil nematode, is a versatilegenetic model system very useful to study genes in many biolog-ical pathways that are evolutionarily conserved. Here, we reviewthe main characteristics of the structure and functions of DCXR, theapproaches to utilize the enzyme as a molecular marker and dis-cuss how studies using C. elegans provide an excellent experimentalmodel for investigation of DCXR-related medical conditions.

2. Biochemical properties

The reduction of l-xylulose to xylitol by DCXR is found in theglucuronate pathway of animal systems, an alternative route of

glucose-6-phosphate oxidation, which also generates l-gulonate,a vitamin C precursor in mammals except hamsters and primates(Fig. 2A) (Kaneko et al., 1997; Linster and Van Schaftingen, 2006).It is reported that the concentration of l-xylulose is increased

2564 S.-K. Lee et al. / The International Journal of Biochemistry & Cell Biology 45 (2013) 2563– 2567

Fig. 1. Functional implications of DCXR. The enzyme is a multi-functional enzyme which plays a pivotal role in sugar metabolism and detoxification of highly reactive� . Geneh

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-dicarbonyl compounds (DCs) that are able to cause serious clinical conditionsemicellulose biomass. (DCXR X-ray image, PDB ID: 1WNT).

n rat livers and liver extracts, along with the enhanced vitamin synthesis, by several xenobiotics including aminopyrine andhloretone. This results from a rapid increase of glucuronate, causedy a removal of inhibition of UDP-glucuronase (Linster and Vanchaftingen, 2006). It is unknown whether l-xylulose reductasectivity is also regulated to meet the demand of l-xylulose reduc-ion in rat livers treated with xenobiotics.

The l-xylulose reductase activity is also required for the pentoseatabolism in certain filamentous fungi and yeasts, which are ableo ferment alcohols from l-arabinose and d-xylose, the two mostbundant hemicellulose-derived pentoses (Fig. 2B) (Fonseca et al.,007). Microbial pentose metabolism has been gaining much inter-st recently, since lignocellulose biomass is regarded as a highlyromising feedstock for a rapidly expanding alcohol fuel industry.s an effort to engineer the industrial fermentative yeast Saccha-omyces cerevisiae originally unable to metabolize l-arabinose,theungal l-arabinose pathway has been stably expresseed (Margeott al., 2009). Modulation of DCXR activity in these arabinose-onsuming yeast strains provides a viable alternative strategy forfficient l-arabinose conversion into ethanol.

DCXRs have been turned out to be diacetyl reductase (EC 1.1.1.5),hich reduces the various DCs involved in the formation of AGEs

Nakagawa et al., 2002). DCs are originated from sugars, or lipidompounds, and generated in various biological systems by oxida-ive stress. DCs undergo a series of non-enzymatic and enzymaticeactions to form a chemically related group of moieties defined asGEs, which remain irreversibly bound to proteins. The accumu-

ated AGEs subsequently induce inflammation and carcinogenesisy activating the receptor for AGE (RAGE) (Kang et al., 2012). Theormation of AGEs can be accelerated in clinical conditions suchs diabetes mellitus, advanced aging and renal failure (Bohlendert al., 2005).

. Molecular structure

DCXR is a member of the short-chain dehydrogenase/reductaseSDR) and aldo-ketoreductase super families (Kavanagh et al.,008). It shares cofactor binding amino acid sequences ofGxxx[AG]xG (Fig. 3A). DCXR is composed of approximately 26-Da subunits and the X-ray crystal structure of human DCXR haseen determined as a homodimer and the quaternary structure ofhe physiological tetramer was reported (Fig. 3B) (Sudo et al., 2005).

The DCXR from yeast, Ambrosiozyma monospora, named ALX1

A. monospora l-xylulose reductase), has been reported to useADH as a dominant cofactor instead of NADPH for its reductasectivity (Verho et al., 2004). ALX1 contains different amino acidequence for the cofactor binding site from other DCXRs using

tic engineering of industrial fungi is a potential strategy to supply biofuel from

NADPH (Fig. 3A). According to the X-ray crystallography structureof human l-xylulose reductase, Lys17, Arg39, and Thr40 are hydro-gen bonding with the phosphate group of NADPH (Fig. 3A and C)(El-Kabbani et al., 2004). These Lys, Arg and Thr are substitutedwith Gly, Glu, and Leu, respectively, in ALX1. This likely confersALX1 binding capacity to NADH, which may play a role to resolve acofactor imbalance generated in the fungal pentose catabolic path-way, in which NADPH is used in the reductions and NAD+ in theoxidations (Fig. 2B) (Verho et al., 2004).

4. Pathogenesis

4.1. Detoxification and osmoregulation

DCXR is highly expressed in livers and kidneys of mam-mals, especially in epithelial cells of mouse proximal renal tubule(Nakagawa et al., 2002). DCXR may play a pivotal role to relieve car-bonyl stress in those organs where DCs are constitutively produceddue to high carbohydrate and lipid metabolisms, or unnecessarilyreabsorbed with diminished tubular reducing capacity with dia-betic environment or renal failure. The study using transgenic miceover-expressing DCXR under kidney-specific promoter supportsthe detoxifying role of DCXR in kidney as documented by accu-mulation of 3-deoxyglucosone, a dicarbonyl hexose (Odani et al.,2008).

Xylitol is an intracellular organic osmolyte with low transep-ithelial permeability, and has been shown to regulate osmolarity inthe epithelium of the lung where DCXR is detected both at mRNAand protein level in mammals including human (Nakagawa et al.,2002; Zabner et al., 2000). The accumulation of xylitol inducescataractous lesions in xylose-fed young rats through glucuronatemetabolism (Goode et al., 1996). The osmoregulation by xylitolis implicated in congenital or infantile cataract, because xylitol ispresent in the lens of affected children (Sulochana et al., 1997).Therefore, in addition to the detoxification of DCs, the concen-trated DCXR in the brush-border membranes of renal tubular cellsmay contribute to maintain osmolarity in the renal tubules andcollecting ducts.

2,3-Pentanedione, 2,3-hexanedione, and 3,4-hexanedione,inhalable butter flavoring DCs, have been reported to cause respi-ratory and olfactory toxicity, or apoptotic and necrotic effects incultured neuroblastoma cells (Hubbs et al., 2012; Zilz et al., 2007).

Thus, it is plausible that DCXR may play a protective role againstvolatile xenobiotic substances which may cause the production oraccumulation of DCs in lungs and eyes which are directly exposedto the air environment.

S.-K. Lee et al. / The International Journal of Biochemistry & Cell Biology 45 (2013) 2563– 2567 2565

Fig. 2. Glucuronate (or urinate) pathway and pentose metabolism in filamentous fungi or xylose-fermenting yeasts. (A) Glucose-6-phosphate is converted to glucose-1-phosphate, which then reacts with uridine 5′-triphosphate (UTP) to form uridine diphosphate glucose (UDPG). UDPG is then oxidized to uridine diphosphoglucuronic acid(UDPGA) and sequentially cleaved to release d-glucuronate and UDP. d-Glucuronate is next reduced to l-gulonate, which is subsequently decarboxylated to become l-xylulose, the substrate for DCXR usingNADPH as a cofactor. (B) l-Arabinose isconverted into l-arabitol, subsequently oxidized to l-xylulose, which DCXR converts to xylitol(also a dehydrogenated alcohol of d-xylose), the entry point into the pentose phosphate pathway leading toward further fermentation. GLO, l-gulonolactone oxidase; PPP,pentose phosphate pathway. *The reaction step catalyzed by DCXR is indicated.

2566 S.-K. Lee et al. / The International Journal of Biochemistry & Cell Biology 45 (2013) 2563– 2567

Fig. 3. Cofactor binding site in DCXR. (A) 3D structure of human DCXR shows mammalian amino acids, K17, R39, and T40 involve in H-bonding with phosphate groupof NADPH (El-Kabbani et al., 2004). (B) R203 interacts with the C-terminus of another monomer to dimerize. (C) Alignment of amino acid sequences of DCXR homologsfrom mouse (MoDCXR; Q91X52), human (HuDCXRP34H; Q7Z4W1), worm (DHS-21; Q21929) and yeast (ALX-1; CAE47547.1). (generated by using Clustal Omega). Solid linei rnvall,T sponda vironm

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ndicates SDR ‘classical’ Subfamily Consensus Sequence,TGxxx[AG]xG(Kavanagh, Johe asterisked Arg203 is substituted with Gly230 in ALX1. R226 in ALX1 at the corre

role for H-bonding to stabilize the DCXR dimer within different 3D topological en

.2. Male fertility and cancers

DCXR, also known as P34H, is an epididymal protein whichs synthesized by the human epididymis, secreted into thepididymal lumen and added to the sperm surface during the epi-idymis transit (Nakagawa et al., 2002; Sullivan, 2004). DCXR haseen suggested to be involved in the interaction of human spermith zona-pellucida, and the loss of DCXR from sperm has been

ssociated with male idiopathic infertility (Moskovtsev et al., 2007).smoregulation in the epididymal environment is essential for

perm maturation accompanying the dramatic reduction of spermucleus volume. This makes it possible to obtain optimal velocityf sperms and to package and protect paternal chromosomes fromutagenic effects (Johnson et al., 2011). Also, high oxidative power

evel of epididymis is required for the intense disulfide bridgingf thiol-containing protamines in sperm (Julianelli and Farrando,012). The intrinsic oxidative stress enhances the chance of DCccumulation in epididymis, and induces various antioxidantnzymatic systems (Noblanc et al., 2012). While potentially pro-iding the direct contact platform for the zona binding, DCXR maylay a role to preserve sperm surface competence for the bindingy protecting the surface proteins from highly active DCs, and/oraintain the sperm nucleus packaging via osmotic balancing.DCXRs are upregulated in melanocytic lesions and prostate

denocarcinoma and might be good candidates for biomarker inifferent the cancers (Cho-Vega et al., 2007a,b). Further investi-ation would contribute to answer the key questions; does thencrease of DCXR activity play a protective or pathological role inhe condition? What substrates do the DCXR reduce? How is theCXR gene expression altered?

.3. Pentosuria

DCXR deficiency leads to pentosuria, a genetic disorder inher-ted as an autosomal recessive (Garrod, 1908). The features of thenborn error were later extensively described in Croonian Lecturen Biochemical Medicine history (Scriver, 2008). In the early 20thentury, clinically benign pentosuria used to be misdiagnoseds diabetes, because a person with pentosuria excretes 2–4 g of-xylulose daily, identified as a positive in the standard diagnosticest of the day which was not able to differentiate between glucosend l-xylulose (Lasker, 1933). Since hexose (glucose)-specificnzyme test papers became standard for urine-tests, these inter-sting cases without any medical complication have not beenecognized. Therefore further research about pentosuria has beenardly performed thereafter, which is an ironic, unfortunateonsequence of the advanced modern clinical practice. That is why

uman genetic research by Motulsky group synthesizes a century-ide effort by dedicated scientists, confirming the lack of the DCXR

ctivity causes the recessively inherited metabolic disorder (Piercet al., 2011). They identify a couple of single nucleotide mutations

2008). The positions of mammalian K17, R39, and T40 are pointed by filled arrows.ing position of human T199 (circled), which is pointed by an open arrow, may playent.

in DCXR responsible for pentosuria in affected Ashkenazi-Jews,an ethnicity where almost all of pentosuria cases are reported,relying on Margaret Lasker’s more than 50-year-old preciousand invaluable pentosuric family records. Both DCXR c.583�Cand DCXR c.52(+1)G > A are predicted to be null, and appearedafter the European origin of the Ashkenazi Jewish population.DCXR c.52(+1)G > A is likely to be a more recent allele than DCXRc.583�C. The question whether those mutant alleles are responsi-ble for the minor cases in South African, Lebanese, Japanese, NorthAmerican families, and even yet-unidentified cases probably callsfor more dedicated scientists’ unremitting exertions.

5. DHS-21: DCXR in C. elegans

Considering the multi-functional enzymatic activity of DCXR,the healthy-in-overall persons with pentosuria may be differen-tially affected under some disease conditions such as diabeticnephropathy, cancers, and cataract. It would be possible to testwhether those clinical conditions are more frequent among theAshkanazi-Jewish individuals with pentosuria. Also, utilizing var-ious model systems to study DCXR functions is encouraged totest hypotheses involving technical and ethical issues such asfertility and longevity. In addition, using genetically versatilemodels provide dissectible research platform to understand molec-ular and cellular mechanisms about the pathologic etiologies.The transgenic mouse model of DCXR successfully shows thatover-expression of DCXR drastically reduces the level of DCs accu-mulated under carbonyl stress elicited by renal unilateral ureteralobstruction (UUO), which causes nephritic condition (Odani et al.,2008). While the DCXR-deficient mouse model has not beenreported yet, which may serve as a mammalian model for pen-tosuria, a recent study of DCXR using C. elegans reveals that thefunction of DCXR is highly conserved in evolution, making theworm model with powerful genetics useful to study the multi-functional enzyme. dhs-21 (jh129), a null worm mutant of DCXR,has a smaller brood size, difficulty in egg-laying, and reducedlifespan(Son le et al., 2011). Dysregulation of osmolarity seems toplay a critical role to exhibit some phenotypes in dhs-21 (jh129)(Lee S.-K., unpublished). DCXR seems to be highly regulated inmammals, because its expression shows a degree of tissue speci-ficity, and up-regulated in several types of cancers (Cho-Vega et al.,2007a,b; Matsunaga et al., 2008; Nakagawa et al., 2002). However,it is largely unknown how the DCXR gene is regulated respond-ing various biological circumstances in mammals. The nematodemodel clearly provides a novel finding that the gene expres-sion of DCXR is highly regulated by transcription factors daf-16and elt-2, FOXO and GATA orthologs, respectively (Son le et al.,

2011). Further studies utilizing molecular biological and biochem-ical methods should continue to investigate the evolutionarilyconserved underlying mechanism of fertility and longevity controlby DCXR.

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cknowledgements

Marek Michalak and Seong Eon Ryu are appreciated for theiraluable comments and suggestions. Hyunsook Hwaang providedxcellent technical support. Hyeon Jeong Lee and Mi Ry Hanre greatly appreciated for illustration support. This research wasupported by Basic Science Research Program through the Nationalesearch Foundation of Korea (NRF) funded by the Ministry ofducation (no. 2013R1A1A2005836), and the Women Scientist pro-ram (no. 2013R1A1A3A04006010) in the Basic Science Researchrogram through the National Research Foundation of Korea (NRF)rant funded by Korean Ministry of Science, ICT & Future Planning.

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