View source for Phosphoglucomutase

{{Short description|Metabolic enzyme}}
{{Enzyme
| Name = Phosphoglucomutase
| EC_number = 5.4.2.2
| CAS_number = 9001-81-4
| GO_code = 
| image = Phosphoglucomutase-1JDY.jpg
| width = 
| caption = Rabbit muscle phosphoglucomutase, drawn from {{PDB|1JDY}}
}}
'''Phosphoglucomutase''' ({{EnzExplorer|5.4.2.2}}) is an [[enzyme]] that transfers a [[phosphate group]] on an α-D-[[glucose]] [[monomer]] from the 1 to the 6 position in the forward direction or the 6 to the 1 position in the reverse direction.

More precisely, it facilitates the interconversion of [[glucose 1-phosphate]] and [[glucose 6-phosphate]].

== Function ==

===Role in glycogenolysis===

After [[glycogen phosphorylase]] catalyzes the phosphorolytic cleavage of a glucosyl residue from the [[glycogen]] [[polymer]], the freed glucose has a [[phosphate]] group on its 1-carbon. This glucose 1-phosphate [[molecule]] is not itself a useful metabolic intermediate, but phosphoglucomutase catalyzes the conversion of this glucose 1-phosphate to glucose 6-phosphate (see below for the mechanism of this reaction).

Glucose 6-phosphate’s metabolic fate depends on the needs of the [[cell (biology)|cell]] at the time it is generated. If the cell is low on energy, then glucose 6-phosphate will travel down the [[glycolysis|glycolytic pathway]], eventually yielding two molecules of [[adenosine triphosphate]]. If the cell is in need of biosynthetic intermediates, glucose 6-phosphate will enter the [[pentose phosphate pathway]], where it will undergo a series of reactions to yield [[ribose]]s and/or [[nicotinamide adenine dinucleotide phosphate|NADPH]], depending on cellular conditions.

If glycogenolysis is taking place in the liver, glucose 6-phosphate can be [[Gluconeogenesis|converted to glucose]] by the enzyme [[glucose 6-phosphatase]]; the glucose produced in the liver is then released to the bloodstream for use in other organs. Muscle cells in contrast do not have the enzyme glucose 6-phosphatase, so they cannot share their glycogen stores with the rest of the body.

===Role in glycogenesis===

Phosphoglucomutase also acts in the opposite fashion when blood glucose levels are high. In this case, phosphoglucomutase catalyzes the conversion of glucose 6-phosphate (which is easily generated from glucose by the action of [[hexokinase]]) to glucose 1-phosphate.

This glucose-1-phosphate can then react with [[uridine triphosphate|UTP]] to yield [[uridine diphosphate glucose|UDP-glucose]] in a reaction catalyzed by [[UTP—glucose-1-phosphate uridylyltransferase|UDP-glucose-pyrophosphorylase]]. If activated by [[insulin]], [[glycogen synthase]] will proceed to clip the glucose from the UDP-glucose complex onto a glycogen polymer.

==Reaction mechanism==

Phosphoglucomutase affects a phosphoryl group shift by exchanging a phosphoryl group with the [[enzyme substrate (biology)|substrate]].<ref>{{cite journal | vauthors = Jagannathan V, Luck JM | title = Phosphoglucomutase; mechanism of action | journal = The Journal of Biological Chemistry | volume = 179 | issue = 2 | pages = 569–575 | date = June 1949 | pmid = 18149991 | doi = 10.1016/S0021-9258(19)51252-2 | doi-access = free }}</ref> [[Isotopic labeling]] experiments have confirmed that this reaction proceeds through a [[glucose 1,6-bisphosphate]] [[reaction intermediate|intermediate]].<ref name="Najjar">{{cite journal | vauthors = Najjar VA, Pullman ME | title = The occurrence of a group transfer involving enzyme (phosphoglucomutase) and substrate | journal = Science | volume = 119 | issue = 3097 | pages = 631–634 | date = May 1954 | pmid = 13156640 | doi = 10.1126/science.119.3097.631 | bibcode = 1954Sci...119..631N }}</ref>

The first step in the forward reaction is the transfer of a phosphoryl group from the enzyme to glucose 1-phosphate, forming glucose 1,6-bisphosphate and leaving a dephosphorylated form of the enzyme.<ref name="Najjar" /> The enzyme then undergoes a rapid diffusional reorientation to position the 1-phosphate of the bisphosphate intermediate properly relative to the dephosphorylated enzyme.<ref>{{cite book|title=The Enzymes|vauthors=Ray Jr WJ, Peck EJ|publisher=Academic Press|year=1972|isbn=978-0-12-122706-7| veditors = Boyer PD|edition=3rd|volume=6|location=New York|pages=407–477|chapter=Phosphomutases|doi=10.1016/S1874-6047(08)60047-5}}</ref> Substrate-velocity relationships and induced transport tests have revealed that the dephosphorylated enzyme then facilitates the transfer of a phosphoryl group from the glucose-1,6-bisphosphate intermediate to the enzyme, regenerating phosphorylated phosphoglucomutase and yielding glucose 6-phosphate (in the forward direction).<ref>{{cite journal | vauthors = Ray WJ, Roscelli GA | title = A Kinetic Study of the Phosphoglucomutase Pathway | journal = The Journal of Biological Chemistry | volume = 239 | issue = 4 | pages = 1228–1236 | date = April 1964 | pmid = 14165931 | doi = 10.1016/S0021-9258(18)91416-X | doi-access = free }}</ref><ref>{{cite journal | vauthors = Britton HG, Clarke JB | title = The mechanism of the phosphoglucomutase reaction. Studies on rabbit muscle phosphoglucomutase with flux techniques | journal = The Biochemical Journal | volume = 110 | issue = 2 | pages = 161–180 | date = November 1968 | pmid = 5726186 | pmc = 1187194 | doi = 10.1042/bj1100161 }}</ref> Later structural studies confirmed that the single site in the enzyme that becomes phosphorylated and dephosphorylated is the oxygen of the [[active site|active-site]] [[serine]] residue (see diagram below).<ref>{{cite journal | vauthors = Ray WJ, Mildvan AS, Grutzner JB | title = Phosphorus nuclear magnetic resonance studies of phosphoglucomutase and its metal ion complexes | journal = Archives of Biochemistry and Biophysics | volume = 184 | issue = 2 | pages = 453–463 | date = December 1977 | pmid = 23074 | doi = 10.1016/0003-9861(77)90455-6 }}</ref><ref>{{cite journal | vauthors = Ray WJ, Hermodson MA, Puvathingal JM, Mahoney WC | title = The complete amino acid sequence of rabbit muscle phosphoglucomutase | journal = The Journal of Biological Chemistry | volume = 258 | issue = 15 | pages = 9166–9174 | date = August 1983 | pmid = 6223925 | doi = 10.1016/S0021-9258(17)44646-1 | doi-access = free }}</ref> A bivalent [[metal]] [[ion]], usually [[magnesium]] or [[cadmium]], is required for enzymatic activity and has been shown to complex directly with the phosphoryl group esterified to the active-site serine.<ref>{{cite journal | vauthors = Rhyu GI, Ray WJ, Markley JL | title = Enzyme-bound intermediates in the conversion of glucose 1-phosphate to glucose 6-phosphate by phosphoglucomutase. Phosphorus NMR studies | journal = Biochemistry | volume = 23 | issue = 2 | pages = 252–260 | date = January 1984 | pmid = 6230103 | doi = 10.1021/bi00297a013 }}</ref>

[[Image:Phosphoglucomutase Mechanism.svg|frame|center|Mechanism for the phosphoglucomutase-catalyzed interconversion of glucose 1-phosphate and glucose 6-phosphate.]]

This formation of a glucose 1,6-bisphosphate intermediate is analogous to the interconversion of [[2-phosphoglyceric acid|2-phosphoglycerate]] and [[3-phosphoglyceric acid|3-phosphoglycerate]] catalyzed by [[phosphoglycerate mutase]], in which [[2,3-bisphosphoglyceric acid|2,3-bisphosphoglycerate]] is generated as an intermediate.<ref>{{cite journal | vauthors = Sutherland EW, Cohn M | title = The mechanism of the phosphoglucomutase reaction | journal = The Journal of Biological Chemistry | volume = 180 | issue = 3 | pages = 1285–1295 | date = October 1949 | pmid = 18148026 | doi = 10.1016/S0021-9258(19)51242-X | doi-access = free }}</ref>

== Structure ==

[[Image:Phosphoglucomutase Four Domains.png|350px|thumb|right|The four domains of rabbit muscle phosphoglucomutase, drawn from {{PDB|1JDY}}. Green = Domain I, Blue = Domain II, Red = Domain III, Yellow = Domain IV. Pink residue = Serine 116.]]

While rabbit muscle phosphoglucomutase has served as the prototype for much of the elucidation of this enzyme's structure, newer [[bacteria|bacterium]]-derived crystal structures exhibit many of the same defining characteristics.<ref>{{cite journal | vauthors = Mehra-Chaudhary R, Mick J, Tanner JJ, Henzl MT, Beamer LJ | title = Crystal structure of a bacterial phosphoglucomutase, an enzyme involved in the virulence of multiple human pathogens | journal = Proteins | volume = 79 | issue = 4 | pages = 1215–1229 | date = April 2011 | pmid = 21246636 | pmc = 3066478 | doi = 10.1002/prot.22957 }}</ref> Each phosphoglucomutase monomer can be divided into four sequence domains, I-IV, based on the enzyme’s default spatial configuration (see image at right).<ref name="Dai">{{cite journal | vauthors = Dai JB, Liu Y, Ray WJ, Konno M | title = The crystal structure of muscle phosphoglucomutase refined at 2.7-angstrom resolution | journal = The Journal of Biological Chemistry | volume = 267 | issue = 9 | pages = 6322–6337 | date = March 1992 | pmid = 1532581 | doi = 10.1016/S0021-9258(18)42699-3 | doi-access = free }}</ref>

Each monomer comprises four distinct α/β structural units, each of which contains one of the four strands in each monomer's [[beta sheet|β-sheet]] and is made up only of the residues in a given sequence domain (see image at right).<ref name="Dai" /> The burial of the active site (including Ser-116, the critical residue on the enzyme that is phosphorylated and dephosphorylated) in the [[hydrophobe|hydrophobic]] interior of the enzyme serves to exclude water from counterproductively [[hydrolysis|hydrolyzing]] critical phosphoester bonds while still allowing the substrate to access the active site.<ref>{{cite journal | vauthors = Ray WJ, Puvathingal JM, Liu YW | title = Formation of substrate and transition-state analogue complexes in crystals of phosphoglucomutase after removing the crystallization salt | journal = Biochemistry | volume = 30 | issue = 28 | pages = 6875–6885 | date = July 1991 | pmid = 1829964 | doi = 10.1021/bi00242a011 }}</ref>

==Disease relevance==

Human muscle contains two [[Isozyme|isoenzymes]] of phosphoglucomutase with nearly identical catalytic properties, PGM I and PGM II.<ref>{{cite journal | vauthors = Joshi JG, Handler P | title = Phosphoglucomutase. VI. Purification and properties of phosphoglucomutases from human muscle | journal = The Journal of Biological Chemistry | volume = 244 | issue = 12 | pages = 3343–3351 | date = June 1969 | pmid = 4978319 | doi = 10.1016/S0021-9258(18)93132-7 | doi-access = free }}</ref> One or the other of these forms is missing in some humans congenitally.<ref>{{cite book|author=Brown DH|title=Myology: Basic and Clinical|publisher=McGraw-Hill|year=1986|isbn=978-0-07-079570-9|location=New York|pages=673–95|chapter=Glycogen metabolism and glycolysis in muscle}}</ref> PGM1 deficiency is known as PGM1-CDG or [[Congenital disorder of glycosylation|CDG syndrome]] type 1t (CDG1T), formerly known as [[glycogen storage disease]] type 14 (GSD XIV).<ref>{{Cite web |title=Orphanet: Glycogen storage disease due to phosphoglucomutase deficiency |url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=711 |access-date=May 13, 2021 |website=www.orpha.net |language=en}}</ref><ref name=":2">{{cite journal | vauthors = Altassan R, Radenkovic S, Edmondson AC, Barone R, Brasil S, Cechova A, Coman D, Donoghue S, Falkenstein K, Ferreira V, Ferreira C, Fiumara A, Francisco R, Freeze H, Grunewald S, Honzik T, Jaeken J, Krasnewich D, Lam C, Lee J, Lefeber D, Marques-da-Silva D, Pascoal C, Quelhas D, Raymond KM, Rymen D, Seroczynska M, Serrano M, Sykut-Cegielska J, Thiel C, Tort F, Vals MA, Videira P, Voermans N, Witters P, Morava E | display-authors = 6 | title = International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management | journal = Journal of Inherited Metabolic Disease | volume = 44 | issue = 1 | pages = 148–163 | date = January 2021 | pmid = 32681750 | pmc = 7855268 | doi = 10.1002/jimd.12286 }}</ref> The disease is both a glycogenosis and a congenital disorder of glycosylation.<ref>{{cite journal | vauthors = Tegtmeyer LC, Rust S, van Scherpenzeel M, Ng BG, Losfeld ME, Timal S, Raymond K, He P, Ichikawa M, Veltman J, Huijben K, Shin YS, Sharma V, Adamowicz M, Lammens M, Reunert J, Witten A, Schrapers E, Matthijs G, Jaeken J, Rymen D, Stojkovic T, Laforêt P, Petit F, Aumaître O, Czarnowska E, Piraud M, Podskarbi T, Stanley CA, Matalon R, Burda P, Seyyedi S, Debus V, Socha P, Sykut-Cegielska J, van Spronsen F, de Meirleir L, Vajro P, DeClue T, Ficicioglu C, Wada Y, Wevers RA, Vanderschaeghe D, Callewaert N, Fingerhut R, van Schaftingen E, Freeze HH, Morava E, Lefeber DJ, Marquardt T | display-authors = 6 | title = Multiple phenotypes in phosphoglucomutase 1 deficiency | journal = The New England Journal of Medicine | volume = 370 | issue = 6 | pages = 533–542 | date = February 2014 | pmid = 24499211 | pmc = 4373661 | doi = 10.1056/NEJMoa1206605 }}</ref><ref name=":3">{{cite journal | vauthors = Stojkovic T, Vissing J, Petit F, Piraud M, Orngreen MC, Andersen G, Claeys KG, Wary C, Hogrel JY, Laforêt P | display-authors = 6 | title = Muscle glycogenosis due to phosphoglucomutase 1 deficiency | journal = The New England Journal of Medicine | volume = 361 | issue = 4 | pages = 425–427 | date = July 2009 | pmid = 19625727 | doi = 10.1056/NEJMc0901158 | doi-access = free }}</ref> It is also a [[metabolic myopathy]] and an [[Inborn errors of carbohydrate metabolism|inborn error of carbohydrate metabolism]].<ref name=":4">{{cite journal | vauthors = Hogrel JY, Janssen JB, Ledoux I, Ollivier G, Béhin A, Stojkovic T, Eymard B, Voermans NC, Laforet P | display-authors = 6 | title = The diagnostic value of hyperammonaemia induced by the non-ischaemic forearm exercise test | journal = Journal of Clinical Pathology | volume = 70 | issue = 10 | pages = 896–898 | date = October 2017 | pmid = 28400468 | doi = 10.1136/jclinpath-2017-204324 | s2cid = 36935686 | url = https://hal.sorbonne-universite.fr/hal-01618833/file/Hogrel_2017_The_diagnostic.pdf }}</ref>

PGM deficiency is an extremely rare condition that does not have a set of well-characterized physiological symptoms. This condition can be detected by an [[in vitro]] study of [[anaerobic glycolysis]] which reveals a block in the pathway toward [[lactic acid]] production after glucose 1-phosphate but before glucose 6-phosphate.<ref>{{cite journal | vauthors = Sugie H, Kobayashi J, Sugie Y, Ichimura M, Miyamoto R, Ito T, Shimizu K, Igarashi Y | display-authors = 6 | title = Infantile muscle glycogen storage disease: phosphoglucomutase deficiency with decreased muscle and serum carnitine levels | journal = Neurology | volume = 38 | issue = 4 | pages = 602–605 | date = April 1988 | pmid = 2965317 | doi = 10.1212/WNL.38.4.602 | s2cid = 11491932 }}</ref> There are two forms of PGM1-CDG: 1.) exclusively myogenic, and 2.) multi-system (including muscles).<ref name=":2" /> 

The usual pathway for glycogen formation from blood [[glucose]] is blocked, as without phosphoglucomutase, glucose-6-phosphate cannot convert into glucose-1-phosphate. However, an alternative pathway from [[galactose]] can form glycogen by converting galactose → galactose-1-phosphate → glucose-1-phosphate. This allows glycogen to form, but without phosphoglucomutase, glucose-1-phosphate cannot convert into glucose-6-phosphate for glycolysis. This causes abnormal glycogen accumulation in muscle cells, observable in muscle biopsy.<ref name=":2" /><ref name=":0">{{Cite web |date=2012-07-11 |title=Congenital Disorder of Glycosylation, Type It; CDG1T |url=https://omim.org/entry/614921 |website=Online Mendelian Inheritance in Man}}</ref>

Although the phenotype and severity of the disease is highly variable, common symptoms include: [[exercise intolerance]], exercise-induced [[hyperammonemia]], abnormal [[glycogen]] accumulation in muscle biopsy, elevated serum CK, abnormal serum [[transferrin]] (loss of complete N-glycans), short stature, cleft palate, bifid uvula, and hepatopathy.<ref name=":2" /><ref name=":0" /> 

A "[[second wind]]" phenomenon is observable in some, but not all, by measuring heart rate while on a treadmill.<ref name=":2" /><ref>{{cite journal | vauthors = Preisler N, Cohen J, Vissing CR, Madsen KL, Heinicke K, Sharp LJ, Phillips L, Romain N, Park SY, Newby M, Wyrick P, Mancias P, Galbo H, Vissing J, Haller RG | display-authors = 6 | title = Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency | journal = Molecular Genetics and Metabolism | volume = 122 | issue = 3 | pages = 117–121 | date = November 2017 | pmid = 28882528 | doi = 10.1016/j.ymgme.2017.08.007 }}</ref> At rest, muscle cells rely on blood glucose and free fatty acids; upon exertion, muscle glycogen is needed along with blood glucose and free fatty acids.<ref name=":1">{{Cite web |title=Berne and Levy Physiology, 6th ed 38. Hormonal Regulation of Energy Metabolism |url=https://doctorlib.info/physiology/physiology/38.html}}</ref><ref name=":5">{{cite journal | vauthors = van Loon LJ, Greenhaff PL, Constantin-Teodosiu D, Saris WH, Wagenmakers AJ | title = The effects of increasing exercise intensity on muscle fuel utilisation in humans | journal = The Journal of Physiology | volume = 536 | issue = Pt 1 | pages = 295–304 | date = October 2001 | pmid = 11579177 | pmc = 2278845 | doi = 10.1111/j.1469-7793.2001.00295.x }}</ref> The reliance on muscle glycogen increases with higher-intensity aerobic exercise and all anaerobic exercise.<ref name=":1" /><ref name=":5" /> 

Without being able to create [[Adenosine triphosphate|ATP]] from stored muscle glycogen, during exercise there is a low ATP reservoir (ADP>ATP). Under such circumstances, the heart rate and breathing increases inappropriately given the exercise intensity, in an attempt to maximize the delivery of oxygen and blood borne fuels to the muscle cell. Free fatty acids are the slowest of the body's [[bioenergetic systems]] to produce ATP by [[oxidative phosphorylation]], at approximately 10 minutes.<ref name=":1" /> The relief of exercise intolerance symptoms, including a drop in heart rate of at least 10 BPM while going the same speed on the treadmill, after approximately 10 minutes of aerobic exercise is called "[[second wind]]," where increased ATP is being produced from free fatty acids. 

Another consequence of a low ATP reservoir (ADP>ATP) during exercise, due to not being able to produce ATP from muscle glycogen, is increased use of the [[Adenylate kinase|myokinase]] (adenylate kinase) reaction and the [[purine nucleotide cycle]]. The myokinase reaction produces AMP (2 ADP → ATP + AMP), and then the purine nucleotide cycle both uses AMP and produces more AMP along with fumarate (the fumarate is then converted and produces ATP via oxidative phosphorylation). Ammonia (NH<sub>3</sub>) is a byproduct in the purine nucleotide cycle when AMP is converted into IMP. During a non-ischemic forearm test, PGM1-CDG individuals show exercise-induced elevated serum ammonia (hyperammonemia) and normal serum lactate rise.<ref name=":2" /><ref name=":3" /><ref name=":4" />

Studies in other diseases that have a glycolytic block have shown during ischemic and non-ischemic forearm exercise tests, that not only does ammonia rise, but after exercise, rises also in serum inosine, hypoxanthine, and uric acid.<ref>{{cite journal | vauthors = Mineo I, Kono N, Hara N, Shimizu T, Yamada Y, Kawachi M, Kiyokawa H, Wang YL, Tarui S | display-authors = 6 | title = Myogenic hyperuricemia. A common pathophysiologic feature of glycogenosis types III, V, and VII | journal = The New England Journal of Medicine | volume = 317 | issue = 2 | pages = 75–80 | date = July 1987 | pmid = 3473284 | doi = 10.1056/NEJM198707093170203 }}</ref><ref>{{cite journal | vauthors = Mineo I, Tarui S | title = Myogenic hyperuricemia: what can we learn from metabolic myopathies? | journal = Muscle & Nerve. Supplement | volume = 3 | pages = S75–S81 | date = 1995 | pmid = 7603532 | doi = 10.1002/mus.880181416 | s2cid = 41588282 }}</ref> These studies supported that when the exercise is stopped or sufficient ATP is produced from other fuels (such as free fatty acids), then the ATP reservoir normalizes and the buildup of AMP and other nucleotides covert into nucleosides and leave the muscle cell to be converted into [[uric acid]], known as [[myogenic hyperuricemia]]. AMP → IMP → Inosine → Hypoxanthine → Xanthine → Uric acid. Unfortunately, the studies on PGM1-CDG only tested for serum ammonia and lactate, so it is currently unknown definitively whether PGM1-CDG individuals also experience myogenic hyperuricemia.<ref name=":2" /><ref name=":3" /><ref name=":4" /> 

==Genes==
* [[PGM1]], [[PGM2]], [[PGM3]], [[PGM5]]

== See also ==
* [[Beta-phosphoglucomutase]]
* [[Congenital disorder of glycosylation]]
* [[Exercise intolerance#Low ATP reservoir in muscles (inherited or acquired)|Exercise intolerance § Low ATP reservoir in muscles]]
* [[Glycogen storage disease]]
* [[Inborn errors of carbohydrate metabolism]]
* [[Metabolic myopathy|Metabolic myopathies]]
* [[Mutase]]
* [[Purine nucleotide cycle]] (ADP>ATP, AMP↑)
* [[Second wind]] (exercise phenomenon)

== References ==
{{reflist}}

== External links ==
* {{MeshName|Phosphoglucomutase}}
{{Inborn errors of carbohydrate metabolism}}{{Glycogenolysis}}
{{Mutases}}
{{Enzymes}}
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[[Category:EC 5.4.2]]