View source for Aldolase A

{{Infobox_gene}}
{{enzyme
| Name = fructose-bisphosphate aldolase
| EC_number = 4.1.2.13
| CAS_number = 9024-52-6
| IUBMB_EC_number = 4/1/2/13
| GO_code = 0004332
| image = 
| width = 
| caption = 
}}
'''Aldolase A''' ('''ALDOA''', or '''ALDA'''), also known as fructose-bisphosphate aldolase, is an [[enzyme]] that in humans is encoded by the ''ALDOA'' gene on chromosome 16.

The protein encoded by this gene is a [[glycolytic]] enzyme that catalyzes the reversible conversion of [[fructose-1,6-bisphosphate]] to [[G3P|glyceraldehyde 3-phosphate]] and [[DHAP|dihydroxyacetone phosphate]]. Three [[aldolase]] isozymes (A, B, and C), encoded by three different genes, are differentially expressed during development. Aldolase A is found in the developing embryo and is produced in even greater amounts in adult muscle. Aldolase A expression is repressed in adult liver, kidney and intestine and similar to [[aldolase C]] levels in brain and other nervous tissue. Aldolase A deficiency has been associated with [[myopathy]] and [[hemolytic anemia]]. [[Alternative splicing]] and alternative promoter usage results in multiple transcript variants. Related [[pseudogene]]s have been identified on chromosomes 3 and 10. [provided by RefSeq, Aug 2011]<ref name="entrez">{{cite web | title = Entrez Gene: ALDOA aldolase A, fructose-bisphosphate| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=226| accessdate = }}</ref>

==Structure==
ALDOA is a [[homotetramer]] and one of the three aldolase isozymes (A, B, and C), encoded by three different genes.<ref name=pmid24465716>{{cite journal|last1=Du|first1=S|last2=Guan|first2=Z|last3=Hao|first3=L|last4=Song|first4=Y|last5=Wang|first5=L|last6=Gong|first6=L|last7=Liu|first7=L|last8=Qi|first8=X|last9=Hou|first9=Z|last10=Shao|first10=S|title=Fructose-bisphosphate aldolase a is a potential metastasis-associated marker of lung squamous cell carcinoma and promotes lung cell tumorigenesis and migration.|journal=PLOS ONE|date=2014|volume=9|issue=1|pages=e85804|pmid=24465716|doi=10.1371/journal.pone.0085804|pmc=3900443|bibcode=2014PLoSO...985804D}}</ref><ref name=pmid14615364>{{cite journal|last1=Yao|first1=DC|last2=Tolan|first2=DR|last3=Murray|first3=MF|last4=Harris|first4=DJ|last5=Darras|first5=BT|last6=Geva|first6=A|last7=Neufeld|first7=EJ|title=Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr).|journal=Blood|date=15 March 2004|volume=103|issue=6|pages=2401–3|pmid=14615364|doi=10.1182/blood-2003-09-3160}}</ref> The ''ALDOA'' gene contains 8 [[exon]]s and the [[5']] [[Untranslated region|UTR]] IB.<ref name=pmid14615364/> Key [[amino acid]]s responsible for its catalytic function have been identified. The [[amino acid|residue]] Tyr363 functions as the acid–base catalyst for protonating C3 of the [[substrate (biochemistry)|substrate]], while Lys146 is proposed to stabilize the negative charge of the resulting [[conjugate base]] of Tyr363 and the strained configuration of the [[C-terminal]]. Residue Glu187 participates in multiple functions, including FBP aldolase catalysis, acid–base catalysis during substrate binding, [[dehydration]], and substrate cleavage.<ref name=pmid25267444>{{cite journal|last1=Tittmann|first1=K|title=Sweet siblings with different faces: the mechanisms of FBP and F6P aldolase, transaldolase, transketolase and phosphoketolase revisited in light of recent structural data.|journal=Bioorganic Chemistry|date=December 2014|volume=57|pages=263–80|pmid=25267444|doi=10.1016/j.bioorg.2014.09.001}}</ref> Though ALDOA localizes to the nucleus, it lacks any known [[nuclear localization signal]]s (NLS).<ref name=pmid23886627>{{cite journal|last1=Mamczur|first1=P|last2=Gamian|first2=A|last3=Kolodziej|first3=J|last4=Dziegiel|first4=P|last5=Rakus|first5=D|title=Nuclear localization of aldolase A correlates with cell proliferation.|journal=Biochimica et Biophysica Acta|date=December 2013|volume=1833|issue=12|pages=2812–22|pmid=23886627|doi=10.1016/j.bbamcr.2013.07.013}}</ref>

==Mechanism==

In mammalian aldolase, the key catalytic [[amino acid]] residues involved in the reaction are [[lysine]] and [[tyrosine]]. The tyrosine acts as an efficient hydrogen acceptor while the lysine covalently binds and stabilizes the intermediates. Many [[bacteria]] use two [[magnesium]] [[ions]] in place of the lysine.

{|
|[[Image:ALDO reaction.png|thumb|400px|<div style="border-width: 0px; border-bottom: 1px solid black; text-align: left;">'''The reaction mechanism of aldolase'''.<br />The enzyme's reactive site amino acid's side-chains are shown in <span style="color: blue; font-weight: bold;">blue</span>.</div>Abbreviations: DHAP - dihydroxyacetone phosphate; Fru1,6bP - Fructose-1,6-bisphosphate; GAD - glyceraldehyde 3-phosphate;]]
|}

{{Complex enzymatic reaction
|major_substrate_1=β-<small>D</small>-[[fructose 1,6-phosphate]]
|major_substrate_1_stoichiometric_constant=
|major_substrate_1_image=beta-D-fructose-1,6-bisphosphate_wpmp.png
|major_substrate_2=
|major_substrate_2_stoichiometric_constant=
|major_substrate_2_image=
|major_product_1=<small>D</small>-[[glyceraldehyde 3-phosphate]]
|major_product_1_stoichiometric_constant=
|major_product_1_image=D-glyceraldehyde-3-phosphate_wpmp.png
|major_product_2=[[dihydroxyacetone phosphate]]
|major_product_2_stoichiometric_constant=
|major_product_2_image=glycerone-phosphate_wpmp.png
|forward_enzyme=[[fructose-bisphosphate aldolase]]
|reverse_enzyme=
|reaction_direction_(forward/reversible/reverse)=reversible
|minor_forward_substrate(s)=
|minor_forward_product(s)=
|minor_reverse_product(s)=
|minor_reverse_substrate(s)=
}}
{{KEGG compound|C05378}} {{KEGG enzyme|4.1.2.13}} {{KEGG compound|C00111}} {{KEGG compound|C00118}}

''The numbering of the carbon atoms indicates the fate of the carbons according to their position in fructose 6-phosphate.''

==Function==
ALDOA is a key enzyme in the fourth step of glycolysis, as well as in the reverse pathway [[gluconeogenesis]]. It catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehydes-3-phosphate and dihydroxyacetone phosphate by [[aldol]] cleavage of the C3–C4 bond. As a result, it is a crucial player in [[Adenosine triphosphate|ATP]] [[biosynthesis]].<ref name=pmid24465716/><ref name=pmid25267444/><ref name=pmid23886627/><ref name=pmid21307348>{{cite journal|last1=Merkulova|first1=M|last2=Hurtado-Lorenzo|first2=A|last3=Hosokawa|first3=H|last4=Zhuang|first4=Z|last5=Brown|first5=D|last6=Ausiello|first6=DA|last7=Marshansky|first7=V|title=Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution.|journal=American Journal of Physiology. Cell Physiology|date=June 2011|volume=300|issue=6|pages=C1442-55|pmid=21307348|doi=10.1152/ajpcell.00076.2010|pmc=3118619}}</ref><ref name=pmid20511553>{{cite journal|last1=Sekar|first1=Y|last2=Moon|first2=TC|last3=Slupsky|first3=CM|last4=Befus|first4=AD|title=Protein tyrosine nitration of aldolase in mast cells: a plausible pathway in nitric oxide-mediated regulation of mast cell function.|journal=Journal of Immunology|date=1 July 2010|volume=185|issue=1|pages=578–87|pmid=20511553|doi=10.4049/jimmunol.0902720}}</ref> ALDOA also contributes to other "moonlighting" functions such as muscle maintenance, regulation of cell shape and motility, [[striated muscle]] [[Muscle contraction|contraction]], [[actin]] [[cytoskeleton]] organization, and regulation of cell proliferation.<ref name=pmid24465716/><ref name=pmid23886627/><ref name=pmid21307348/> ALDOA likely regulates actin cytoskeleton remodeling through interacting with [[cytohesin-2]] (ARNO) and Arf6.<ref name=pmid21307348/>

ALDOA is ubiquitously expressed in most tissues, though it is predominantly expressed in developing embryo and adult muscle.<ref name=pmid24465716/><ref name=pmid20511553/> In [[lymphocyte]]s, ALDOA is the predominant aldolase isoform.<ref name=pmid20511553/> Within the cell, ALDOA typically [[subcellular localization|localizes]] to the [[cytoplasm]], but it can localize to the [[Cell nucleus|nucleus]] during [[DNA synthesis]] of the [[cell cycle]] S phase. This nuclear localization is regulated by the protein [[kinase]]s [[AKT]] and [[p38 mitogen-activated protein kinases|p38]]. It is suggested that the nucleus serves as a reservoir for ALDOA in low glucose conditions.<ref name=pmid23886627/> ALDOA has also been found in [[mitochondria]].<ref name=pmid20511553/>

ALDOA is regulated by the energy metabolism substrates [[glucose]], [[lactic acid|lactate]], and [[glutamine]].<ref name=pmid23886627/> In human [[mast cell]]s (MCs), ALDOA has been observed to undergo post-translational regulation by protein [[tyrosine]] [[nitration]], which may alter its relative [[affinity (pharmacology)|affinity]] for [[Fructose 1,6-bisphosphate|FBP]] and/or [[Inositol trisphosphate|IP3]]. This change then affects IP3 and PLC [[signal transduction|signaling cascades]] in IgE-dependent responses.<ref name=pmid20511553/>

==Clinical significance==
Aldolase A (ALDOA) is a highly expressed in multiple cancers, including [[lung squamous cell carcinoma]] (LSCC), [[renal cancer]], and [[hepatocellular carcinoma]]. It is proposed that ALDOA overexpression enhances glycolysis in these tumor cells, promoting their growth. In LSCC, its upregulation correlates with [[metastasis]] and poor prognosis, while its downregulation reduces tumor cell motility and [[tumorigenesis]]. Thus, ALDOA could be a potential LSCC [[biomarker]] and therapeutic drug target.<ref name=pmid24465716/>

[[Aldolase A deficiency]] is a rare, [[autosomal]] [[recessive]] disorder that is linked to [[hemolysis]] and accompanied by weakness, muscle pain, and [[myopathy]].<ref name=pmid14615364/>

==Interactive pathway map==
{{GlycolysisGluconeogenesis_WP534|highlight=Aldolase_A}}

==Interactions==
Aldolase A has been shown to [[Protein-protein interaction|interact]] with: 
*[[PLD2]],<ref name=pmid11876650>{{cite journal |last=Kim |first=Jong Hyun |authorlink= |author2=Lee Sukmook|author3=Kim Jung Hwan|author4=Lee Taehoon G|author5=Hirata Masato|author6=Suh Pann-Ghill|author7=Ryu Sung Ho |date=Mar 2002 |title=Phospholipase D2 directly interacts with aldolase via Its PH domain |journal=Biochemistry |volume=41 |issue=10 |pages=3414–21 |publisher= |location = United States| issn = 0006-2960| pmid = 11876650 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |doi=10.1021/bi015700a }}</ref> 
*[[actin]],<ref name=pmid20511553/>
*[[GLUT4]],<ref name=pmid17329259>{{cite journal|last1=St-Jean|first1=M|last2=Izard|first2=T|last3=Sygusch|first3=J|title=A hydrophobic pocket in the active site of glycolytic aldolase mediates interactions with Wiskott-Aldrich syndrome protein.|journal=The Journal of Biological Chemistry|date=11 May 2007|volume=282|issue=19|pages=14309–15|pmid=17329259|doi=10.1074/jbc.m611505200}}</ref>
*[[phospholipase]] D2,<ref name=pmid17329259/>
*light chain 8 of [[dynein]],<ref name=pmid17329259/> 
*erythrocyte anion exchanger Band 3 protein,<ref name=pmid17329259/>
*[[ryanodine receptor]],<ref name=pmid20511553/>
*[[Cytohesin-2]],<ref name=pmid21307348/> and
*[[V-ATPase]] (vacuolar-type H+-ATPase).<ref name=pmid21307348/>

==See also==
*[[ALDOB]]
*[[ALDOC]]
*[[Fructose-bisphosphate aldolase]]

==References==
{{reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal  |vauthors=Pfleiderer G, Thöner M, Wachsmuth ED |title=Histological examination of the aldolase monomer composition of cells from human kidney and hypernephroid carcinoma |journal=Beiträge zur Pathologie |volume=156 |issue= 3 |pages= 266–79 |year= 1976 |pmid= 766744 |doi=  10.1016/s0005-8165(75)80166-1}}
*{{cite journal  |vauthors=Rehbein-Thöner M, Pfleiderer G |title=The changes in aldolase isoenzyme pattern during development of the human kidney and small intestine--demonstrated in organ extracts and tissue sections |journal=Hoppe-Seyler's Z. Physiol. Chem. |volume=358 |issue= 2 |pages= 169–80 |year= 1977 |pmid= 844801 |doi=  10.1515/bchm2.1977.358.1.169}}
*{{cite journal  | author=Wachsmuth ED |title=Differentiation of epithelial cells in human jejunum: localization and quantification of aminopeptidase, alkaline phosphatase and aldolase isozymes in tissue sections |journal=Histochemistry |volume=48 |issue= 2 |pages= 101–9 |year= 1976 |pmid= 955981 |doi=10.1007/BF00494548  }}
*{{cite journal  |vauthors=Lee KN, Maxwell MD, Patterson MK |title=Identification of transglutaminase substrates in HT29 colon cancer cells: use of 5-(biotinamido)pentylamine as a transglutaminase-specific probe |journal=Biochim. Biophys. Acta |volume=1136 |issue= 1 |pages= 12–6 |year= 1992 |pmid= 1353685 |doi=10.1016/0167-4889(92)90078-P  |display-authors=etal}}
*{{cite journal  |vauthors=Dawson SJ, White LA |title=Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin |journal=J. Infect. |volume=24 |issue= 3 |pages= 317–20 |year= 1992 |pmid= 1602151 |doi=10.1016/S0163-4453(05)80037-4  }}
*{{cite journal  |vauthors=Mukai T, Arai Y, Yatsuki H |title=An additional promoter functions in the human aldolase A gene, but not in rat |journal=Eur. J. Biochem. |volume=195 |issue= 3 |pages= 781–7 |year= 1991 |pmid= 1999195 |doi=10.1111/j.1432-1033.1991.tb15766.x  |display-authors=etal}}
*{{cite journal  |vauthors=Gamblin SJ, Davies GJ, Grimes JM |title=Activity and specificity of human aldolases |journal=J. Mol. Biol. |volume=219 |issue= 4 |pages= 573–6 |year= 1991 |pmid= 2056525 |doi=10.1016/0022-2836(91)90650-U  |display-authors=etal}}
*{{cite journal  |vauthors=Vértessy BG, Orosz F, Ovádi J |title=Modulation of the interaction between aldolase and glycerol-phosphate dehydrogenase by fructose phosphates |journal=Biochim. Biophys. Acta |volume=1078 |issue= 2 |pages= 236–42 |year= 1991 |pmid= 2065091 |doi=  10.1016/0167-4838(91)90564-g}}
*{{cite journal  |vauthors=Takasaki Y, Takahashi I, Mukai T, Hori K |title=Human aldolase A of a hemolytic anemia patient with Asp-128----Gly substitution: characteristics of an enzyme generated in E. coli transfected with the expression plasmid pHAAD128G |journal=J. Biochem. |volume=108 |issue= 2 |pages= 153–7 |year= 1990 |pmid= 2229018 |doi=  }}
*{{cite journal  |vauthors=Gamblin SJ, Cooper B, Millar JR |title=The crystal structure of human muscle aldolase at 3.0 A resolution |journal=FEBS Lett. |volume=262 |issue= 2 |pages= 282–6 |year= 1990 |pmid= 2335208 |doi=10.1016/0014-5793(90)80211-Z  |display-authors=etal}}
*{{cite journal  |vauthors=Kishi H, Mukai T, Hirono A |title=Human aldolase A deficiency associated with a hemolytic anemia: thermolabile aldolase due to a single base mutation |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 23 |pages= 8623–7 |year= 1988 |pmid= 2825199 |doi=10.1073/pnas.84.23.8623  | pmc=299598  |display-authors=etal|bibcode=1987PNAS...84.8623K}}
*{{cite journal  |vauthors=Izzo P, Costanzo P, Lupo A |title=A new human species of aldolase A mRNA from fibroblasts |journal=Eur. J. Biochem. |volume=164 |issue= 1 |pages= 9–13 |year= 1987 |pmid= 3030757 |doi=10.1111/j.1432-1033.1987.tb10984.x  |display-authors=etal}}
*{{cite journal  |vauthors=Inagaki H, Haimoto H, Hosoda S, Kato K |title=Aldolase C is localized in neuroendocrine cells |journal=Experientia |volume=44 |issue= 9 |pages= 749–51 |year= 1988 |pmid= 3046960 |doi=10.1007/BF01959149  }}
*{{cite journal  |vauthors=Freemont PS, Dunbar B, Fothergill-Gilmore LA |title=The complete amino acid sequence of human skeletal-muscle fructose-bisphosphate aldolase |journal=Biochem. J. |volume=249 |issue= 3 |pages= 779–88 |year= 1988 |pmid= 3355497 |doi=  | pmc=1148774  }}
*{{cite journal  |vauthors=Izzo P, Costanzo P, Lupo A |title=Human aldolase A gene. Structural organization and tissue-specific expression by multiple promoters and alternate mRNA processing |journal=Eur. J. Biochem. |volume=174 |issue= 4 |pages= 569–78 |year= 1988 |pmid= 3391172 |doi=10.1111/j.1432-1033.1988.tb14136.x  |display-authors=etal}}
*{{cite journal  |vauthors=Maire P, Gautron S, Hakim V |title=Characterization of three optional promoters in the 5' region of the human aldolase A gene |journal=J. Mol. Biol. |volume=197 |issue= 3 |pages= 425–38 |year= 1988 |pmid= 3441006 |doi=10.1016/0022-2836(87)90556-0  |display-authors=etal}}
*{{cite journal  |vauthors=Kukita A, Yoshida MC, Fukushige S |title=Molecular gene mapping of human aldolase A (ALDOA) gene to chromosome 16 |journal=Hum. Genet. |volume=76 |issue= 1 |pages= 20–6 |year= 1987 |pmid= 3570299 |doi=10.1007/BF00283044  |display-authors=etal}}
*{{cite journal  |vauthors=Tolan DR, Niclas J, Bruce BD, Lebo RV |title=Evolutionary implications of the human aldolase-A, -B, -C, and -pseudogene chromosome locations |journal=Am. J. Hum. Genet. |volume=41 |issue= 5 |pages= 907–24 |year= 1987 |pmid= 3674018 |doi=  | pmc=1684339  }}
*{{cite journal  |vauthors=Sakakibara M, Mukai T, Hori K |title=Nucleotide sequence of a cDNA clone for human aldolase: a messenger RNA in the liver |journal=Biochem. Biophys. Res. Commun. |volume=131 |issue= 1 |pages= 413–20 |year= 1985 |pmid= 3840020 |doi=10.1016/0006-291X(85)91818-2  }}
*{{cite journal  |vauthors=Ovádi J, Mohamed Osman IR, Batke J |title=Interaction of the dissociable glycerol-3-phosphate dehydrogenase and fructose-1,6-bisphosphate aldolase. Quantitative analysis by an extrinsic fluorescence probe |journal=Eur. J. Biochem. |volume=133 |issue= 2 |pages= 433–7 |year= 1983 |pmid= 6406231 |doi=10.1111/j.1432-1033.1983.tb07482.x  }}
{{refend}}

==External links==
* http://pdbdev.sdsc.edu:48346/pdb/molecules/pdb50_5.html{{Dead link|date=October 2018 |bot=InternetArchiveBot |fix-attempted=yes }}
* {{MeshName|Fructose-Bisphosphate+Aldolase}}
* {{Gene|ALDOA}}
* {{EC number|4.1.2.13}}
* {{UCSC gene info|ALDOA}}

{{PDB Gallery|geneid=226}}
{{glycolysis}}
{{Carbon-carbon lyases}}
{{Glycolysis enzymes}}

[[Category:Enzymes]]