Aldolase A: Difference between revisions

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{{Infobox_gene}}
{{PBB_Controls
{{enzyme
| update_page = yes
| Name = fructose-bisphosphate aldolase
| require_manual_inspection = no
| EC_number = 4.1.2.13
| update_protein_box = yes
| CAS_number = 9024-52-6
| update_summary = yes
| IUBMB_EC_number = 4/1/2/13
| update_citations = yes
| 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 GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
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>
{{GNF_Protein_box
 
| image = Fructose-1,6-bisphosphate aldolase 4ALD wpmp.png
==Structure==
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 4ALD.
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}}</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>
| PDB = {{PDB2|1ado}}, {{PDB2|1ald}}, {{PDB2|1ewd}}, {{PDB2|1ewe}}, {{PDB2|1ewg}}, {{PDB2|1ex5}}, {{PDB2|1j4e}}, {{PDB2|1zah}}, {{PDB2|1zai}}, {{PDB2|1zaj}}, {{PDB2|1zal}}, {{PDB2|2ald}}, {{PDB2|2ot0}}, {{PDB2|2ot1}}, {{PDB2|4ald}}, {{PDB2|6ald}}
 
| Name = Aldolase A, fructose-bisphosphate
==Mechanism==
| HGNCid = 414
 
| Symbol = ALDOA
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.
| AltSymbols =; ALDA; MGC10942; MGC17716; MGC17767
 
| OMIM = 103850
{|
| ECnumber =
|[[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;]]
| Homologene = 68996
|}
| MGIid = 87994
| GeneAtlas_image1 = PBB_GE_ALDOA_200966_x_at_tn.png
| GeneAtlas_image2 = PBB_GE_ALDOA_214687_x_at_tn.png
| Function = {{GNF_GO|id=GO:0004332 |text = fructose-bisphosphate aldolase activity}} {{GNF_GO|id=GO:0016829 |text = lyase activity}}
| Component =  
| Process = {{GNF_GO|id=GO:0006000 |text = fructose metabolic process}} {{GNF_GO|id=GO:0006096 |text = glycolysis}} {{GNF_GO|id=GO:0006941 |text = striated muscle contraction}} {{GNF_GO|id=GO:0008152 |text = metabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 226
    | Hs_Ensembl = ENSG00000149925
    | Hs_RefseqProtein = NP_000025
    | Hs_RefseqmRNA = NM_000034
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 16
    | Hs_GenLoc_start = 29971973
    | Hs_GenLoc_end = 29989235
    | Hs_Uniprot = P04075
    | Mm_EntrezGene = 11674
    | Mm_Ensembl = ENSMUSG00000030695
    | Mm_RefseqmRNA = NM_007438
    | Mm_RefseqProtein = NP_031464
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 7
    | Mm_GenLoc_start = 126586384
    | Mm_GenLoc_end = 126590331
    | Mm_Uniprot = Q5FWB7
  }}
}}
'''Aldolase A''' is an [[enzyme]] which catalyses one of the [[aldol reactions]]: The [[substrate (biochemistry)|substrate]], [[fructose 1,6-bisphosphate]] (F-1,6-BP) is broken down into [[glyceraldehyde 3-phosphate]] and [[dihydroxyacetone phosphate]] ([[DHAP]]). This [[reaction]] is a part of [[glycolysis]]. 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 of this gene results in multiple transcript variants which encode the same protein.<ref name="entrez">{{cite web | title = Entrez Gene: ALDOA aldolase A, fructose-bisphosphate| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=226| accessdate = }}</ref>


{{ Complex Enzymatic Reaction
{{Complex enzymatic reaction
|major_substrate_1=β-<small>D</small>-[[fructose 1,6-phosphate]]
|major_substrate_1=β-<small>D</small>-[[fructose 1,6-phosphate]]
|major_substrate_1_stoichiometric_constant=
|major_substrate_1_stoichiometric_constant=
Line 62: Line 38:
|major_product_2_stoichiometric_constant=
|major_product_2_stoichiometric_constant=
|major_product_2_image=glycerone-phosphate_wpmp.png
|major_product_2_image=glycerone-phosphate_wpmp.png
|foward_enzyme=[[fructose bisphosphate aldolase]]
|forward_enzyme=[[fructose-bisphosphate aldolase]]
|reverse_enzyme=[[fructose bisphosphate aldolase]]
|reverse_enzyme=
|reaction_direction_(foward/reversible/reverse)=reversible
|reaction_direction_(forward/reversible/reverse)=reversible
|minor_foward_substrate(s)=
|minor_forward_substrate(s)=
|minor_foward_product(s)=
|minor_forward_product(s)=
|minor_reverse_product(s)=
|minor_reverse_product(s)=
|minor_reverse_substrate(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/>


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


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


In mammalian aldolase the key catylitic [[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.
==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/>


[[Image:ALDO_reaction.png|thumb|center|573px|<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;]]
==See also==
*[[ALDOB]]
*[[ALDOC]]
*[[Fructose-bisphosphate aldolase]]


==References==
==References==
{{reflist|2}}
{{reflist}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
*{{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}}
| citations =
*{{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=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=  }}
*{{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  | author=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=  }}
*{{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  | 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=  }}
*{{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  | author=Lee KN, Maxwell MD, Patterson MK, ''et al.'' |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= }}
*{{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  | author=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=  }}
*{{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  | author=Mukai T, Arai Y, Yatsuki H, ''et al.'' |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=  }}
*{{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  | author=Gamblin SJ, Davies GJ, Grimes JM, ''et al.'' |title=Activity and specificity of human aldolases. |journal=J. Mol. Biol. |volume=219 |issue= 4 |pages= 573-6 |year= 1991 |pmid= 2056525 |doi=  }}
*{{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  | author=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=  }}
*{{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  | author=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=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}}
*{{cite journal  | author=Gamblin SJ, Cooper B, Millar JR, ''et al.'' |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= }}
*{{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  | author=Kishi H, Mukai T, Hirono A, ''et al.'' |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=  }}
*{{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  | author=Izzo P, Costanzo P, Lupo A, ''et al.'' |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=  }}
*{{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  | author=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=  }}
*{{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  | author=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=  }}
*{{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  | author=Izzo P, Costanzo P, Lupo A, ''et al.'' |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=  }}
*{{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  | author=Maire P, Gautron S, Hakim V, ''et al.'' |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=  }}
*{{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  | author=Kukita A, Yoshida MC, Fukushige S, ''et al.'' |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=  }}
*{{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  | author=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=  }}
*{{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 }}
*{{cite journal  | author=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=  }}
*{{cite journal  | author=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=  }}
}}
{{refend}}
{{refend}}


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* {{Gene|ALDOA}}
* {{Gene|ALDOA}}
* {{EC number|4.1.2.13}}
* {{EC number|4.1.2.13}}
* {{UCSC gene info|ALDOA}}


{{metabolic pathway stub|enzyme}}
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{{Carbon-carbon lyases}}
{{Carbon-carbon lyases}}
{{Glycolysis enzymes}}
{{Glycolysis enzymes}}
[[Category:Enzymes]]
[[Category:Enzymes]]
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Revision as of 16:47, 27 November 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human
fructose-bisphosphate aldolase
Identifiers
EC number4.1.2.13
CAS number9024-52-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

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 and 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 pseudogenes have been identified on chromosomes 3 and 10. [provided by RefSeq, Aug 2011][1]

Structure

ALDOA is a homotetramer and one of the three aldolase isozymes (A, B, and C), encoded by three different genes.[2][3] The ALDOA gene contains 8 exons and the 5' UTR IB.[3] Key amino acids responsible for its catalytic function have been identified. The residue Tyr363 functions as the acid–base catalyst for protonating C3 of the 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.[4] Though ALDOA localizes to the nucleus, it lacks any known nuclear localization signals (NLS).[5]

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.

The reaction mechanism of aldolase.
The enzyme's reactive site amino acid's side-chains are shown in blue.
Abbreviations: DHAP - dihydroxyacetone phosphate; Fru1,6bP - Fructose-1,6-bisphosphate; GAD - glyceraldehyde 3-phosphate;
β-D-fructose 1,6-phosphate fructose-bisphosphate aldolase D-glyceraldehyde 3-phosphate dihydroxyacetone phosphate
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File:Biochem reaction arrow reversible NNNN horiz med.svg

Compound C05378 at KEGG Pathway Database. Enzyme 4.1.2.13 at KEGG Pathway Database. Compound C00111 at KEGG Pathway Database. Compound C00118 at KEGG Pathway Database.

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 ATP biosynthesis.[2][4][5][6][7] ALDOA also contributes to other "moonlighting" functions such as muscle maintenance, regulation of cell shape and motility, striated muscle contraction, actin cytoskeleton organization, and regulation of cell proliferation.[2][5][6] ALDOA likely regulates actin cytoskeleton remodeling through interacting with cytohesin-2 (ARNO) and Arf6.[6]

ALDOA is ubiquitously expressed in most tissues, though it is predominantly expressed in developing embryo and adult muscle.[2][7] In lymphocytes, ALDOA is the predominant aldolase isoform.[7] Within the cell, ALDOA typically localizes to the cytoplasm, but it can localize to the nucleus during DNA synthesis of the cell cycle S phase. This nuclear localization is regulated by the protein kinases AKT and p38. It is suggested that the nucleus serves as a reservoir for ALDOA in low glucose conditions.[5] ALDOA has also been found in mitochondria.[7]

ALDOA is regulated by the energy metabolism substrates glucose, lactate, and glutamine.[5] In human mast cells (MCs), ALDOA has been observed to undergo post-translational regulation by protein tyrosine nitration, which may alter its relative affinity for FBP and/or IP3. This change then affects IP3 and PLC signaling cascades in IgE-dependent responses.[7]

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.[2]

Aldolase A deficiency is a rare, autosomal recessive disorder that is linked to hemolysis and accompanied by weakness, muscle pain, and myopathy.[3]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Glycolysis and Gluconeogenesis edit
  1. ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".

Interactions

Aldolase A has been shown to interact with:

See also

References

  1. ↑ "Entrez Gene: ALDOA aldolase A, fructose-bisphosphate".
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Du, S; Guan, Z; Hao, L; Song, Y; Wang, L; Gong, L; Liu, L; Qi, X; Hou, Z; Shao, S (2014). "Fructose-bisphosphate aldolase a is a potential metastasis-associated marker of lung squamous cell carcinoma and promotes lung cell tumorigenesis and migration". PLOS ONE. 9 (1): e85804. doi:10.1371/journal.pone.0085804. PMC 3900443. PMID 24465716.
  3. ↑ 3.0 3.1 3.2 Yao, DC; Tolan, DR; Murray, MF; Harris, DJ; Darras, BT; Geva, A; Neufeld, EJ (15 March 2004). "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)". Blood. 103 (6): 2401–3. doi:10.1182/blood-2003-09-3160. PMID 14615364.
  4. ↑ 4.0 4.1 Tittmann, K (December 2014). "Sweet siblings with different faces: the mechanisms of FBP and F6P aldolase, transaldolase, transketolase and phosphoketolase revisited in light of recent structural data". Bioorganic Chemistry. 57: 263–80. doi:10.1016/j.bioorg.2014.09.001. PMID 25267444.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Mamczur, P; Gamian, A; Kolodziej, J; Dziegiel, P; Rakus, D (December 2013). "Nuclear localization of aldolase A correlates with cell proliferation". Biochimica et Biophysica Acta. 1833 (12): 2812–22. doi:10.1016/j.bbamcr.2013.07.013. PMID 23886627.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Merkulova, M; Hurtado-Lorenzo, A; Hosokawa, H; Zhuang, Z; Brown, D; Ausiello, DA; Marshansky, V (June 2011). "Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution". American Journal of Physiology. Cell Physiology. 300 (6): C1442–55. doi:10.1152/ajpcell.00076.2010. PMC 3118619. PMID 21307348.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 Sekar, Y; Moon, TC; Slupsky, CM; Befus, AD (1 July 2010). "Protein tyrosine nitration of aldolase in mast cells: a plausible pathway in nitric oxide-mediated regulation of mast cell function". Journal of Immunology. 185 (1): 578–87. doi:10.4049/jimmunol.0902720. PMID 20511553.
  8. ↑ Kim, Jong Hyun; Lee Sukmook; Kim Jung Hwan; Lee Taehoon G; Hirata Masato; Suh Pann-Ghill; Ryu Sung Ho (Mar 2002). "Phospholipase D2 directly interacts with aldolase via Its PH domain". Biochemistry. United States. 41 (10): 3414–21. doi:10.1021/bi015700a. ISSN 0006-2960. PMID 11876650.
  9. ↑ 9.0 9.1 9.2 9.3 St-Jean, M; Izard, T; Sygusch, J (11 May 2007). "A hydrophobic pocket in the active site of glycolytic aldolase mediates interactions with Wiskott-Aldrich syndrome protein". The Journal of Biological Chemistry. 282 (19): 14309–15. doi:10.1074/jbc.m611505200. PMID 17329259.

Further reading

External links

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2 × Pyruvate

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