View source for UTP—glucose-1-phosphate uridylyltransferase

{{Short description|Class of enzymes}}
{{infobox enzyme
| Name       = UTP—glucose-1-phosphate uridylyltransferase
| EC_number  = 2.7.7.9
| CAS_number = 9026-22-6
| GO_code    = 0003983
| image      = HUDP-glucose pyrophosphorylase pymol.png
| width      =
| caption    = Human UTP—glucose-1-phosphate uridylyltransferase cartoon created in pymol
| name       = UTP—glucose-1-phosphate uridylyltransferase 
}}

'''UTP—glucose-1-phosphate uridylyltransferase''' also known as '''glucose-1-phosphate uridylyltransferase''' (or '''UDP–glucose pyrophosphorylase''') is an enzyme involved in [[carbohydrate metabolism]]. It synthesizes [[UDP-glucose]] from [[glucose-1-phosphate]] and [[Uridine 5'-triphosphate|UTP]]; i.e.,
: [[glucose-1-phosphate]] + [[Uridine 5'-triphosphate|UTP]] <math>\rightleftharpoons</math> [[UDP-glucose]] + [[pyrophosphate]]
UTP—glucose-1-phosphate uridylyltransferase is an enzyme found in all three [[Domain (biology)|domains]] ([[bacteria]], [[Eukaryote|eukarya]], and [[archaea]]) as it is a key player in [[glycogenesis]] and [[cell wall]] synthesis. Its role in sugar metabolism has been studied extensively in plants in order to understand plant growth and increase agricultural production. Recently, [[human]] UTP—glucose-1-phosphate uridylyltransferase has been studied and crystallized, revealing a different type of regulation than other organisms previously studied. Its significance is derived from the many uses of UDP-glucose including [[galactose]] metabolism, [[Glycogenesis|glycogen synthesis]], [[glycoprotein]] synthesis, and [[glycolipid]] synthesis.<ref>{{cite journal | vauthors = Sandhoff K, van Echten G, Schröder M, Schnabel D, Suzuki K | title = Metabolism of glycolipids: the role of glycolipid-binding proteins in the function and pathobiochemistry of lysosomes | journal = Biochemical Society Transactions | volume = 20 | issue = 3 | pages = 695–9 | date = August 1992 | pmid = 1426613 | doi = 10.1042/bst0200695 }}</ref><ref>{{cite journal | vauthors = Alonso MD, Lomako J, Lomako WM, Whelan WJ | title = A new look at the biogenesis of glycogen | journal = FASEB Journal | volume = 9 | issue = 12 | pages = 1126–37 | date = September 1995 | pmid = 7672505 | doi = 10.1096/fasebj.9.12.7672505 | doi-access = free | s2cid = 40281321 }}</ref>

== Structure ==
The structure of UTP—glucose-1-phosphate uridylyltransferase is significantly different between [[prokaryote]]s and [[eukaryote]]s, but within eukaryotes, the primary, secondary, and tertiary structures of the enzyme are quite conserved.<ref name=":3">{{cite journal | vauthors = Führing JI, Cramer JT, Schneider J, Baruch P, Gerardy-Schahn R, Fedorov R | title = A quaternary mechanism enables the complex biological functions of octameric human UDP-glucose pyrophosphorylase, a key enzyme in cell metabolism | language = en | journal = Scientific Reports | volume = 5 | issue = 1 | pages = 9618 | date = April 2015 | pmid = 25860585 | pmc = 5381698 | doi = 10.1038/srep09618| bibcode = 2015NatSR...5E9618F }}</ref> In many species, UTP—glucose-1-phosphate uridylyltransferase is found as a [[homopolymer]] consisting of identical subunits in a symmetrical quaternary structure.<ref>{{cite journal | vauthors = Kim H, Choi J, Kim T, Lokanath NK, Ha SC, Suh SW, Hwang HY, Kim KK | title = Structural basis for the reaction mechanism of UDP-glucose pyrophosphorylase | journal = Molecules and Cells | volume = 29 | issue = 4 | pages = 397–405 | date = April 2010 | pmid = 20238176 | doi = 10.1007/s10059-010-0047-6  | s2cid = 25022544 | doi-access = free }}</ref><ref name=":1">{{cite journal | vauthors = Thoden JB, Holden HM | title = Active site geometry of glucose-1-phosphate uridylyltransferase | journal = Protein Science | volume = 16 | issue = 7 | pages = 1379–88 | date = July 2007 | pmid = 17567737 | pmc = 2206702 | doi = 10.1110/ps.072864707 }}</ref> The number of subunits varies across species: for instance, in [[Escherichia coli]], the enzyme is found as a tetramer, whereas in [[Burkholderia xenovorans]], the enzyme is dimeric.<ref name=":1" /><ref>{{Cite journal|last=Disease|first=Seattle Structural Genomics Center for Infectious|title=Crystal structure of UDP-glucose pyrophosporylase / UTP-glucose-1-phosphate uridylyltransferase from Burkholderia xenovorans|url=http://www.rcsb.org/pdb/explore/explore.do?structureId=5J49|journal=Worldwide Protein Data Bank|language=en|doi=10.2210/pdb5j49/pdb|year=2016}}</ref> In humans and in yeast, the enzyme is active as an octamer consisting of two tetramers stacked onto one another with conserved hydrophobic residues at the interfaces between the subunits.<ref name=":0">{{cite journal | vauthors = Yu Q, Zheng X | title = The crystal structure of human UDP-glucose pyrophosphorylase reveals a latch effect that influences enzymatic activity | journal = The Biochemical Journal | volume = 442 | issue = 2 | pages = 283–91 | date = March 2012 | pmid = 22132858 | doi = 10.1042/BJ20111598 }}</ref><ref name=":2">{{cite journal | vauthors = Roeben A, Plitzko JM, Körner R, Böttcher UM, Siegers K, Hayer-Hartl M, Bracher A | title = Structural basis for subunit assembly in UDP-glucose pyrophosphorylase from Saccharomyces cerevisiae | journal = Journal of Molecular Biology | volume = 364 | issue = 4 | pages = 551–60 | date = December 2006 | pmid = 17010990 | doi = 10.1016/j.jmb.2006.08.079  }}</ref> In contrast, the enzyme in plants has conserved charged residues forming the interface between subunits.

In humans, each enzyme subunit contains several residues (L113, N251, and N328) that are highly conserved in eukaryotes. A [[Rossmann fold|Rossman fold]] motif participates in binding of the [[Uridine triphosphate|UTP]] [[nucleotide]] and a sugar-binding domain (residues T286–G293) coordinates with the glucose ring.<ref>{{cite journal | vauthors = Kleczkowski LA, Geisler M, Fitzek E, Wilczynska M | title = A common structural blueprint for plant UDP-sugar-producing pyrophosphorylases | journal = The Biochemical Journal | volume = 439 | issue = 3 | pages = 375–9 | date = November 2011 | pmid = 21992098 | doi = 10.1042/BJ20110730 | url = https://pub.uni-bielefeld.de/record/2920898 }}</ref> A [[missense mutation]] (G115D) in the region of the enzyme containing the active site (which is conserved in eukaryotes) causes a dramatic decrease in enzymatic activity in vitro.<ref>{{cite journal | vauthors = Flores-Díaz M, Alape-Girón A, Persson B, Pollesello P, Moos M, von Eichel-Streiber C, Thelestam M, Florin I | title = Cellular UDP-glucose deficiency caused by a single point mutation in the UDP-glucose pyrophosphorylase gene | journal = The Journal of Biological Chemistry | volume = 272 | issue = 38 | pages = 23784–91 | date = September 1997 | pmid = 9295324 | doi=10.1074/jbc.272.38.23784| doi-access = free }}</ref><gallery widths="400" heights="300">
File:Crystal structure of UTP-glucose-1-phosphate uridylyltransferase from Burkholderia xenovorans.png|Crystal structure of UTP—glucose-1-phosphate uridylyltransferase from Burkholderia xenovorans
File:Human UDP-glucose pyrophosphorylase isoform 1 subunit in complex with UDP-glucose.png|Human UTP—glucose-1-phosphate uridylyltransferase isoform 1 subunit with UDP-glucose bound
</gallery>

== Examples ==
Human genes encoding proteins with UTP—glucose-1-phosphate uridylyltransferase activity include two [[Protein isoform|isoforms]] with molecular weights of 56.9 and 55.7 kDa, respectively.<ref name=":4">{{Cite web|url=https://www.uniprot.org/uniprot/Q16851|title=UGP2 - UTP--glucose-1-phosphate uridylyltransferase - Homo sapiens (Human) - UGP2 gene & protein|website=www.uniprot.org|language=en|access-date=2017-03-06}}</ref>
{|
|- valign="top"
|{{infobox protein
|Name=UDP&ndash;glucose pyrophosphorylase 1
|caption=UDP-glucose pyrophosphorylase 1, homooctamer, Human
|image=4r7p.jpg
|width=270
|HGNCid=12526
|Symbol=UGP1
|AltSymbols=
|EntrezGene=7359
|OMIM=191750
|RefSeq=
|UniProt=
|PDB=
|ECnumber=2.7.7.9
|Chromosome=1
|Arm=q
|Band=21
|LocusSupplementaryData=-q22
}}
|{{infobox protein
|Name=UDP&ndash;glucose pyrophosphorylase 2
|caption=
|image=
|width=
|HGNCid=12527
|Symbol=UGP2
|AltSymbols=
|EntrezGene=7360
|OMIM=191760
|RefSeq=NM_006759
|UniProt=Q16851
|PDB=
|ECnumber=2.7.7.9
|Chromosome=2
|Arm=p
|Band=14
|LocusSupplementaryData=-p13
}}
|}

== Function ==

UTP—glucose-1-phosphate uridylyltransferase is ubiquitous in nature due to its important role in the generation of [[Uridine diphosphate glucose|UDP-glucose]], a central compound in carbohydrate metabolism. In plant leaves, UTP—glucose-1-phosphate uridylyltransferase is a key part of the sucrose [[biosynthesis]] pathway, supplying [[Uridine diphosphate glucose]] to [[Sucrose-phosphate synthase]] which converts UDP-glucose and D-[[fructose 6-phosphate]] into sucrose-6-phosphate.<ref>{{cite journal | vauthors = Mendicino J | title = Sucrose phosphate synthesis in wheat germ and green leaves | journal = The Journal of Biological Chemistry | volume = 235 | pages = 3347–52 | date = December 1960 | issue = 12 | doi = 10.1016/S0021-9258(18)64469-2 | pmid = 13769376 | doi-access = free }}</ref> It may also be partially responsible for the breakdown of sucrose in other tissues using UDP-glucose.

In higher animals, the enzyme is highly active in tissues involved in [[glycogenesis]], including the [[liver]] and the [[muscle]]s.<ref>{{Cite book|title=The Enzymes|last1=Turnquist|first1=Richard L.|last2=Hansen|first2=R. Gaurth|date=1973-01-01|publisher=Academic Press|editor-last=Boyer|editor-first=Paul D.|series=Group Transfer Part A: Nucleotidyl Transfer Nucleosidyl Transfer Acyl Transfer Phosphoryl Transfer|volume=8|pages=51–71|doi=10.1016/S1874-6047(08)60062-1|chapter=2 Uridine Diphosphoryl Glucose Pyrophosphorylase|isbn=9780121227081}}</ref> An exception is the [[brain]], which has high levels of [[glycogen]] but low [[Enzyme assay#Specific activity|specific activity]] of UTP—glucose-1-phosphate uridylyltransferase.<ref>{{cite journal | vauthors = Villar-Palasi C, Larner J | title = Insulin-mediated effect on the activity of UDPG-glycogen transglucosylase of muscle | journal = Biochimica et Biophysica Acta | volume = 39 | pages = 171–3 | date = March 1960 | pmid = 13842294 | doi=10.1016/0006-3002(60)90142-6}}</ref> In animal cells, UTP—glucose-1-phosphate uridylyltransferase is found predominantly in the cytoplasm.

UTP—glucose-1-phosphate uridylyltransferase is also required for [[Galactose#Metabolism|galactose metabolism]] in animals and microorganisms. In galactose metabolism, the enzyme galactose 1-phosphate uridylyltransferase transfers a phosphate from UDP-glucose to galactose 1-phosphate to produce UDP-galactose, which is then converted to UDP-glucose.<ref>{{cite journal | vauthors = Bosch AM | title = Classical galactosaemia revisited | journal = Journal of Inherited Metabolic Disease | volume = 29 | issue = 4 | pages = 516–25 | date = August 2006 | pmid = 16838075 | doi = 10.1007/s10545-006-0382-0  | s2cid = 16382462 }}</ref> Bacteria with defective UTP—glucose-1-phosphate uridylyltransferase are unable to incorporate galactose into their cell walls.<ref>{{cite journal | vauthors = Sundararajan TA, Rapin AM, Kalckar HM | title = Biochemical observations on E. coli mutants defective in uridine diphosphoglucose | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 48 | issue = 12 | pages = 2187–93 | date = December 1962 | pmid = 13979281 | pmc = 221142  | doi=10.1073/pnas.48.12.2187| bibcode = 1962PNAS...48.2187S | doi-access = free }}</ref>

==Mechanism==
In this enzyme's primary reaction, the phosphate group on [[glucose-1-phosphate]] replaces the phosphoanhydride bond on UTP. This reaction is readily reversible and the [[Gibbs Free Energy]]  is close to zero. However, under typical cellular conditions, [[inorganic pyrophosphatase]] quickly hydrolyzes the [[pyrophosphate]] product and drives the reaction forward by [[Le Chatelier's principle|Le Chatelier's Principle]].

UTP—glucose-1-phosphate uridylyltransferase uses an [[Enzyme kinetics#Ternary-complex mechanisms|ordered sequential]] Bi Bi mechanism for both the forward and reverse reactions.<ref>{{cite journal | vauthors = Tsuboi KK, Fukunaga K, Petricciani JC | title = Purification and specific kinetic properties of erythrocyte uridine diphosphate glucose pyrophosphorylase | journal = The Journal of Biological Chemistry | volume = 244 | issue = 3 | pages = 1008–15 | date = February 1969 | doi = 10.1016/S0021-9258(18)91886-7 | pmid = 5782905 | doi-access = free }}</ref> In yeast, the enzyme follows simple [[Michaelis–Menten kinetics|Michaelis-Menten kinetics]] and does not exhibit [[cooperativity]] between the subunits in the octamer.<ref name=":2" />

Similar to other sugar [[nucleotidyltransferase]]s, UTP—glucose-1-phosphate uridylyltransferase activity requires two divalent cations to stabilize the binding of negatively charged phosphate groups.<ref>{{cite journal | vauthors = Zea CJ, Camci-Unal G, Pohl NL | title = Thermodynamics of binding of divalent magnesium and manganese to uridine phosphates: implications for diabetes-related hypomagnesaemia and carbohydrate biocatalysis | language = En | journal = Chemistry Central Journal | volume = 2 | issue = 1 | pages = 15 | date = July 2008 | pmid = 18627619 | doi = 10.1186/1752-153x-2-15 | pmc=2490692 | doi-access = free }}</ref> [[Magnesium]] typically serves in this role, but other ions such as [[manganese]](II), [[cobalt]](II), and [[nickel]](II) can also substitute with a ~75% reduction in the optimal activity.<ref>{{cite journal | vauthors = Gustafson GL, Gander JE | title = Uridine diphosphate glucose pyrophosphorylase from Sorghum vulgare. Purification and kinetic properties | language = en | journal = The Journal of Biological Chemistry | volume = 247 | issue = 5 | pages = 1387–97 | date = March 1972 | doi = 10.1016/S0021-9258(19)45571-3 | pmid = 5012314 | url = http://www.jbc.org/content/247/5/1387 | doi-access = free }}</ref> X-ray crystallography experiments have shown that one Mg<sup>2+</sup> ion is coordinated by a phosphoryl oxygen on glucose 1-phosphate and by an α-phosphoryl oxygen on UTP.<ref name=":1" /> In addition to stabilizing the negatively charged phosphates, Mg<sup>2+</sup> is thought to orient the glucose 1-phosphate for [[nucleophilic attack]] of the α-phosphorus of UTP.<ref>{{cite journal | vauthors = Sivaraman J, Sauvé V, Matte A, Cygler M | title = Crystal structure of Escherichia coli glucose-1-phosphate thymidylyltransferase (RffH) complexed with dTTP and Mg2+ | journal = The Journal of Biological Chemistry | volume = 277 | issue = 46 | pages = 44214–9 | date = November 2002 | pmid = 12171937 | doi = 10.1074/jbc.M206932200  | doi-access = free }}</ref>
[[File:UTP—glucose-1-phosphate uridylyltransferase mechanism.png|alt=Mechanism|none|thumb|1050x1050px|UTP—glucose-1-phosphate uridylyltransferase reaction mechanism]]

== Regulation ==

Although functionally similar across species, UDP-glucose pyrophosphorylase has different structures and regulation mechanisms in different organisms.

=== Microorganisms ===
In yeast, UTP—glucose-1-phosphate uridylyltransferase is regulated by phosphorylation by [[PASK|PAS kinase]].<ref>{{cite journal | vauthors = Rutter J, Probst BL, McKnight SL | title = Coordinate regulation of sugar flux and translation by PAS kinase | journal = Cell | volume = 111 | issue = 1 | pages = 17–28 | date = October 2002 | pmid = 12372297 | doi=10.1016/s0092-8674(02)00974-1| s2cid = 6883785 | doi-access = free }}</ref> This phosphorylation is reversible and controls the partition of sugar flux towards glycogen and cell wall synthesis.

===Plants===
UTP—glucose-1-phosphate uridylyltransferase in [[plants]] is regulated through [[oligomerization]] and possibly [[phosphorylation]].<ref>{{cite journal | vauthors = Kleczkowski LA, Geisler M, Ciereszko I, Johansson H | title = UDP-glucose pyrophosphorylase. An old protein with new tricks | journal = Plant Physiology | volume = 134 | issue = 3 | pages = 912–8 | date = March 2004 | pmid = 15020755 | doi = 10.1104/pp.103.036053 | pmc=523891}}</ref> In barley, it has been shown that UDP-glucose pyrophosphorylase is only active in monomeric form but readily forms [[oligomers]], suggesting that oligomerization may be a form of regulation of the enzyme. In rice, cold stress decreases N-[[glycosylation]] of the enzyme, which is thought to alter the enzyme's activity in response to cold.<ref>{{cite journal | vauthors = Komatsu S, Yamada E, Furukawa K | title = Cold stress changes the concanavalin A-positive glycosylation pattern of proteins expressed in the basal parts of rice leaf sheaths | language = en | journal = Amino Acids | volume = 36 | issue = 1 | pages = 115–23 | date = January 2009 | pmid = 18278531 | doi = 10.1007/s00726-008-0039-4 | s2cid = 1797342 }}</ref>

In [[Arabidopsis]], there are two [[isozyme]]s of UTP—glucose-1-phosphate uridylyltransferase: UGP1 and UGP2.<ref>{{cite journal | vauthors = Meng M, Geisler M, Johansson H, Harholt J, Scheller HV, Mellerowicz EJ, Kleczkowski LA | title = UDP-glucose pyrophosphorylase is not rate limiting, but is essential in Arabidopsis | language = en | journal = Plant & Cell Physiology | volume = 50 | issue = 5 | pages = 998–1011 | date = May 2009 | pmid = 19366709 | doi = 10.1093/pcp/pcp052 | doi-access = free }}</ref> These two isozymes have almost identical activities and differ in only 32 amino acids, all of which are located on the outer surface of the protein away from the active site. These minor differences may allow for differential allosteric regulation of isozyme activity. UGP1 and UGP2 are differentially expressed in different parts of the plant. UGP1 expression is widely expressed in the majority of tissues while UGP2 is expressed primarily in flowers, suggesting that UGP1 is the major form of the enzyme and UGP2 serves an auxiliary function. Indeed, UGP2 expression is increased in response to stressors such as phosphate deficiency, indicating that UGP2 probably functions as a backup to UGP1 when the plant is under environmental stress.

=== Animals ===
The control of UTP—glucose-1-phosphate uridylyltransferase activity is primarily achieved by genetic means (i.e. regulation of [[Transcription (biology)|transcription]] and [[Translation (biology)|translation]]). Similar to most enzymes, UTP—glucose-1-phosphate uridylyltransferase is inhibited by its product, UDP-glucose. However, the enzyme is not subject to significant [[allosteric regulation]], which is logical given the widespread use of UDP-glucose in a variety of metabolic pathways.

===Humans===
In humans, UDP-glucose pyrophosphorylase is active as an octamer.<ref name=":0" /> The enzyme's activity is also modified by O-[[glycosylation]].<ref>{{Cite journal|last1=Wells|first1=Lance|last2=Hart|first2=Gerald W.|date=2003-07-03|title=O-GlcNAc turns twenty: functional implications for post-translational modification of nuclear and cytosolic proteins with a sugar|journal=FEBS Letters|language=en|volume=546|issue=1|pages=154–158|doi=10.1016/S0014-5793(03)00641-0|pmid=12829252|s2cid=24587552|issn=1873-3468|doi-access=free}}</ref> Similar to other mamallian species, there two different isoforms in humans that are produced by [[alternative splicing]] of the gene.<ref name=":3" /><ref name=":4" /><ref>{{cite journal | vauthors = Duggleby RG, Chao YC, Huang JG, Peng HL, Chang HY|author-link5=Howard Y. Chang | title = Sequence differences between human muscle and liver cDNAs for UDPglucose pyrophosphorylase and kinetic properties of the recombinant enzymes expressed in Escherichia coli | journal = European Journal of Biochemistry | volume = 235 | issue = 1–2 | pages = 173–9 | date = January 1996 | pmid = 8631325 | doi=10.1111/j.1432-1033.1996.00173.x}}</ref> The isoforms differ by only 11 amino acids at the N-terminus and no significant differences in their functional activity have been identified.

== Disease relevance ==

In humans, [[galactosemia]] is a disorder that affects the development of newborns and children as they cannot metabolize the sugar [[galactose]] properly. It is speculated that overexpression of UDP-glucose pyrophosphorylase may relieve symptoms in humans with galactosemia.<ref>{{cite journal | vauthors = Lai K, Elsas LJ | title = Overexpression of human UDP-glucose pyrophosphorylase rescues galactose-1-phosphate uridyltransferase-deficient yeast | journal = Biochemical and Biophysical Research Communications | volume = 271 | issue = 2 | pages = 392–400 | date = May 2000 | pmid = 10799308 | doi = 10.1006/bbrc.2000.2629 }}</ref>

In [[cancer]] cells, which typically have high rates of [[glycolysis]] and decreased [[glycogen]] content, the activity of UTP—glucose-1-phosphate uridylyltransferase is often downregulated by up to 50-60% compared to normal cells.<ref>{{cite journal | vauthors = Nigam VN, Macdonald HL, Cantero A | title = Limiting factors for glycogen storage in tumors. I. Limiting enzymes | language = en | journal = Cancer Research | volume = 22 | issue = 2 | pages = 131–8 | date = February 1962 | pmid = 14479721 | url = http://cancerres.aacrjournals.org/content/22/2/131 }}</ref> The abnormally low activity of UTP—glucose-1-phosphate uridylyltransferase is due to decreased levels of the enzyme and the downregulation of other enzymes in the glycogenic pathway including [[Glycogen synthetase|glycogen synthase]] and [[phosphoglucomutase]].

UTP—glucose-1-phosphate uridylyltransferase has been found to be an important virulence factor in a variety of pathogens including bacteria and protozoa.<ref>{{cite journal | vauthors = Jiang SS, Lin TY, Wang WB, Liu MC, Hsueh PR, Liaw SJ | title = Characterization of UDP-glucose dehydrogenase and UDP-glucose pyrophosphorylase mutants of Proteus mirabilis: defectiveness in polymyxin B resistance, swarming, and virulence | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 5 | pages = 2000–9 | date = May 2010 | pmid = 20160049 | pmc = 2863647 | doi = 10.1128/AAC.01384-09  }}</ref><ref>{{cite journal | vauthors = Klein KA, Fukuto HS, Pelletier M, Romanov G, Grabenstein JP, Palmer LE, Ernst R, Bliska JB | title = A transposon site hybridization screen identifies galU and wecBC as important for survival of Yersinia pestis in murine macrophages | journal = Journal of Bacteriology | volume = 194 | issue = 3 | pages = 653–62 | date = February 2012 | pmid = 22139502 | pmc = 3264090 | doi = 10.1128/JB.06237-11  }}</ref> For example, the enzyme has been found to be required for the biosynthesis of capsular polysaccharide, an important [[virulence factor]] of ''[[Streptococcus pneumoniae]]'', a bacterial cause of pneumonia, bronchitis, and other breathing issues.<ref>{{cite journal | vauthors = Bonofiglio L, García E, Mollerach M | title = Biochemical characterization of the pneumococcal glucose 1-phosphate uridylyltransferase (GalU) essential for capsule biosynthesis | journal = Current Microbiology | volume = 51 | issue = 4 | pages = 217–21 | date = October 2005 | pmid = 16132460 | doi = 10.1007/s00284-005-4466-0 | s2cid = 13591083 }}</ref> As a result, the enzyme has attracted attention as a potential target for pharmaceuticals. However, in order to achieve specificity, the drugs must be designed to specifically target allosteric sites on the surface of the protein because the active site is highly conserved across species.<ref name=":3" />

UDP-glucose pyrophosphorylase (''UGP2'') was recently found to be implicated in novel neurodevelopmental disorder in humans, known as <ref name="pmid31820119">{{cite journal | vauthors = Perenthaler E, Nikoncuk A, Yousefi S, Berdowski WM, Alsagob M, Capo I, etal | title = Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases | journal = Acta Neuropathologica | volume = 139 | issue = 3 | pages = 415–442 | date = March 2020 | pmid = 31820119 | pmc = 7035241 | doi = 10.1007/s00401-019-02109-6 }}</ref> also referred to as [[Barakat-Perenthaler syndrome]].<ref>{{cite web | title = #618744: Epileptic Encephalopathy, Early Infantile 83; EIEE83 | url = https://www.omim.org/entry/618744 | work = Online Mendelian Inheritance in Man (OMIM) }}</ref> This disorder was first described in 22 individuals from 15 families, presenting with a severe epileptic encephalopathy, neurodevelopmental delay with absence of virtually all developmental milestones, intractable seizures, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Barakat and colleagues identified a recurrent homozygous mutation in all affected individuals (chr2:64083454A > G), which mutates the translational start site of the shorter protein isoform of UGP2. Therefore, the shorter protein isoform can no longer be produced in patients harboring the homozygous mutation. Functional studies from the same group showed that the short protein isoform is normally predominantly expressed in human brain. Therefore, the recurrent mutation leads to a tissue-specific absence of UGP2 in brain, which leads to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation. Other bi-allelic loss-of-function mutations in ''UGP2'' are likely lethal, as human embryonic stem cells depleted of both short and long isoforms of UGP2 fail to differentiate in cardiomyocytes and blood cells. Hence, the identification of this new disease also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. A therapy for Barakat-Perenthaler syndrome does currently not exist.

== References ==
{{Reflist|33em}}

== External links ==
* {{MeshName|UDP+Glucose+Pyrophosphorylase}}

{{Glycogenesis and glycogenolysis}}
{{Kinases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

{{DEFAULTSORT:UTP-glucose-1-phosphate uridylyltransferase}}
[[Category:EC 2.7.7]]