View source for Aldolase A

{{Short description|Mammalian protein found in Homo sapiens}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox_gene}}
{{infobox enzyme
| Name       = fructose-bisphosphate aldolase
| EC_number  = 4.1.2.13
| CAS_number = 9024-52-6
| 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 [[glyceraldehyde 3-phosphate]] (G3P) and [[dihydroxyacetone phosphate]] (DHAP). 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.<ref name="entrez">{{cite web | title = Entrez Gene: ALDOA aldolase A, fructose-bisphosphate | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=226 }}</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 | vauthors = Du S, Guan Z, Hao L, Song Y, Wang L, Gong L, Liu L, Qi X, Hou Z, Shao 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 | volume = 9 | issue = 1 | article-number = e85804 | date = 2014 | pmid = 24465716 | pmc = 3900443 | doi = 10.1371/journal.pone.0085804 | bibcode = 2014PLoSO...985804D | doi-access = free }}</ref><ref name=pmid14615364>{{cite journal | vauthors = Yao DC, Tolan DR, Murray MF, Harris DJ, Darras BT, Geva A, Neufeld 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 | volume = 103 | issue = 6 | pages = 2401–2403 | date = 15 March 2004 | pmid = 14615364 | doi = 10.1182/blood-2003-09-3160 | doi-access = free }}</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 | vauthors = Tittmann 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 | volume = 57 | pages = 263–280 | date = December 2014 | 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 | vauthors = Mamczur P, Gamian A, Kolodziej J, Dziegiel P, Rakus D | title = Nuclear localization of aldolase A correlates with cell proliferation. | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1833 | issue = 12 | pages = 2812–2822 | date = December 2013 | pmid = 23886627 | doi = 10.1016/j.bbamcr.2013.07.013 | doi-access = }}</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. {{Citation needed|date=March 2023}}

{|
|[[Image:ALDO reaction.png|class=skin-invert-image|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 | vauthors = Merkulova M, Hurtado-Lorenzo A, Hosokawa H, Zhuang Z, Brown D, Ausiello DA, Marshansky V | title = Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution. | journal = American Journal of Physiology. Cell Physiology | volume = 300 | issue = 6 | pages = C1442–55 | date = June 2011 | pmid = 21307348 | pmc = 3118619 | doi = 10.1152/ajpcell.00076.2010 }}</ref><ref name=pmid20511553>{{cite journal | vauthors = Sekar Y, Moon TC, Slupsky CM, Befus 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 | location = Baltimore, Md. | volume = 185 | issue = 1 | pages = 578–587 | date = 1 July 2010 | pmid = 20511553 | doi = 10.4049/jimmunol.0902720 | doi-access = free }}</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 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 | vauthors = Kim JH, Lee S, Kim JH, Lee TG, Hirata M, Suh PG, Ryu SH | title = Phospholipase D2 directly interacts with aldolase via Its PH domain | journal = Biochemistry | location = United States | volume = 41 | issue = 10 | pages = 3414–3421 | date = Mar 2002 | pmid = 11876650 | doi = 10.1021/bi015700a | issn = 0006-2960 }}</ref> 
*[[actin]],<ref name=pmid20511553/>
*[[GLUT4]],<ref name=pmid17329259>{{cite journal | vauthors = St-Jean M, Izard T, Sygusch 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 | volume = 282 | issue = 19 | pages = 14309–14315 | date = 11 May 2007 | pmid = 17329259 | doi = 10.1074/jbc.m611505200 | doi-access = free }}</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 = 266–279 | 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 Zeitschrift für Physiologische Chemie | volume = 358 | issue = 2 | pages = 169–180 | year = 1977 | pmid = 844801 | doi = 10.1515/bchm2.1977.358.1.169 }}
*{{cite journal | vauthors = 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 = 101–109 | year = 1976 | pmid = 955981 | doi = 10.1007/BF00494548 | s2cid = 6347675 }}
*{{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 = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1136 | issue = 1 | pages = 12–16 | year = 1992 | pmid = 1353685 | doi = 10.1016/0167-4889(92)90078-P }}
*{{cite journal | vauthors = Dawson SJ, White LA | title = Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin | journal = The Journal of Infection | volume = 24 | issue = 3 | pages = 317–320 | 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 = European Journal of Biochemistry | volume = 195 | issue = 3 | pages = 781–787 | year = 1991 | pmid = 1999195 | doi = 10.1111/j.1432-1033.1991.tb15766.x | doi-access = }}
*{{cite journal | vauthors = Gamblin SJ, Davies GJ, Grimes JM | title = Activity and specificity of human aldolases | journal = Journal of Molecular Biology | volume = 219 | issue = 4 | pages = 573–576 | year = 1991 | pmid = 2056525 | doi = 10.1016/0022-2836(91)90650-U }}
*{{cite journal | vauthors = Vértessy BG, Orosz F, Ovádi J | title = Modulation of the interaction between aldolase and glycerol-phosphate dehydrogenase by fructose phosphates | journal = Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology | volume = 1078 | issue = 2 | pages = 236–242 | 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 = Journal of Biochemistry | volume = 108 | issue = 2 | pages = 153–157 | year = 1990 | pmid = 2229018 | doi = 10.1093/oxfordjournals.jbchem.a123174 | doi-access = free }}
*{{cite journal | vauthors = Gamblin SJ, Cooper B, Millar JR | title = The crystal structure of human muscle aldolase at 3.0 A resolution | journal = FEBS Letters | volume = 262 | issue = 2 | pages = 282–286 | year = 1990 | pmid = 2335208 | doi = 10.1016/0014-5793(90)80211-Z | bibcode = 1990FEBSL.262..282G | s2cid = 46133456 }}
*{{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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 23 | pages = 8623–8627 | year = 1988 | pmid = 2825199 | pmc = 299598 | doi = 10.1073/pnas.84.23.8623 | bibcode = 1987PNAS...84.8623K | doi-access = free }}
*{{cite journal | vauthors = Izzo P, Costanzo P, Lupo A | title = A new human species of aldolase A mRNA from fibroblasts | journal = European Journal of Biochemistry | volume = 164 | issue = 1 | pages = 9–13 | year = 1987 | pmid = 3030757 | doi = 10.1111/j.1432-1033.1987.tb10984.x }}
*{{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 = 749–751 | year = 1988 | pmid = 3046960 | doi = 10.1007/BF01959149 | s2cid = 10109239 }}
*{{cite journal | vauthors = Freemont PS, Dunbar B, Fothergill-Gilmore LA | title = The complete amino acid sequence of human skeletal-muscle fructose-bisphosphate aldolase | journal = The Biochemical Journal | volume = 249 | issue = 3 | pages = 779–788 | year = 1988 | pmid = 3355497 | pmc = 1148774 | doi = 10.1042/bj2490779 }}
*{{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 = European Journal of Biochemistry | volume = 174 | issue = 4 | pages = 569–578 | year = 1988 | pmid = 3391172 | doi = 10.1111/j.1432-1033.1988.tb14136.x | doi-access = free }}
*{{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 = Journal of Molecular Biology | volume = 197 | issue = 3 | pages = 425–438 | year = 1988 | pmid = 3441006 | doi = 10.1016/0022-2836(87)90556-0 }}
*{{cite journal | vauthors = Kukita A, Yoshida MC, Fukushige S | title = Molecular gene mapping of human aldolase A (ALDOA) gene to chromosome 16 | journal = Human Genetics | volume = 76 | issue = 1 | pages = 20–26 | year = 1987 | pmid = 3570299 | doi = 10.1007/BF00283044 | s2cid = 162055 }}
*{{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 = American Journal of Human Genetics | volume = 41 | issue = 5 | pages = 907–924 | year = 1987 | pmid = 3674018 | 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 = Biochemical and Biophysical Research Communications | volume = 131 | issue = 1 | pages = 413–420 | year = 1985 | pmid = 3840020 | doi = 10.1016/0006-291X(85)91818-2 | bibcode = 1985BBRC..131..413S }}
*{{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 = European Journal of Biochemistry | volume = 133 | issue = 2 | pages = 433–437 | year = 1983 | pmid = 6406231 | doi = 10.1111/j.1432-1033.1983.tb07482.x | doi-access = free }}
{{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}}
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P04075 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Fructose-bisphosphate aldolase A
{{PDB Gallery|geneid=226}}
{{glycolysis}}

{{Carbon-carbon lyases}}
{{Glycolysis enzymes}}

[[Category:Enzymes]]
[[Category:Glycolysis]]