Fructose-bisphosphate aldolase

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Fructose-bisphosphate aldolase
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Fructose-bisphosphate aldolase octamer, Human
Identifiers
EC no. 4.1.2.13
CAS no. 9024-52-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
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PMC articles
PubMed articles
NCBI proteins
Fructose-bisphosphate aldolase class-I
PDB 1fdj EBI.jpg
fructose 1,6-bisphosphate aldolase from rabbit liver
Identifiers
SymbolGlycolytic
Pfam PF00274
InterPro IPR000741
PROSITE PDOC00143
SCOP2 1ald / SCOPe / SUPFAM
CDD cd00344
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Fructose-bisphosphate aldolase class-II
PDB 1b57 EBI.jpg
class II fructose-1,6-bisphosphate aldolase in complex with phosphoglycolohydroxamate
Identifiers
SymbolF_bP_aldolase
Pfam PF01116
Pfam clan CL0036
InterPro IPR000771
PROSITE PDOC00523
SCOP2 1dos / SCOPe / SUPFAM
CDD cd00453
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Fructose-bisphosphate aldolase (EC 4.1.2.13), often just aldolase, is an enzyme catalyzing a reversible reaction that splits the aldol, fructose 1,6-bisphosphate, into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P). Aldolase can also produce DHAP from other (3S,4R)-ketose 1-phosphates such as fructose 1-phosphate and sedoheptulose 1,7-bisphosphate. Gluconeogenesis and the Calvin cycle, which are anabolic pathways, use the reverse reaction. Glycolysis, a catabolic pathway, uses the forward reaction. Aldolase is divided into two classes by mechanism.

Contents

The word aldolase also refers, more generally, to an enzyme that performs an aldol reaction (creating an aldol) or its reverse (cleaving an aldol), such as Sialic acid aldolase, which forms sialic acid. See the list of aldolases.

Mechanism and structure

Class I proteins form a protonated Schiff base intermediate linking a highly conserved active site lysine with the DHAP carbonyl carbon. Additionally, tyrosine residues are crucial to this mechanism in acting as stabilizing hydrogen acceptors. Class II proteins use a different mechanism which polarizes the carbonyl group with a divalent cation like Zn2+. The Escherichia coli galactitol operon protein, gatY, and N-acetyl galactosamine operon protein, agaY, which are tagatose-bisphosphate aldolase, are homologs of class II fructose-bisphosphate aldolase. Two histidine residues in the first half of the sequence of these homologs have been shown to be involved in binding zinc. [1]

The protein subunits of both classes each have an α/β domain folded into a TIM barrel containing the active site. Several subunits are assembled into the complete protein. The two classes share little sequence identity.

With few exceptions only class I proteins have been found in animals, plants, and green algae. [2] With few exceptions only class II proteins have been found in fungi. Both classes have been found widely in other eukaryotes and in bacteria. [3] The two classes are often present together in the same organism. Plants and algae have plastidal aldolase, sometimes a relic of endosymbiosis, in addition to the usual cytosolic aldolase. A bifunctional fructose-bisphosphate aldolase/phosphatase, with class I mechanism, has been found widely in archaea and in some bacteria. [4] The active site of this archaeal aldolase is also in a TIM barrel.

In gluconeogenesis and glycolysis

Gluconeogenesis and glycolysis share a series of six reversible reactions. In gluconeogenesis glyceraldehyde-3-phosphate is reduced to fructose 1,6-bisphosphate with aldolase. In glycolysis fructose 1,6-bisphosphate is made into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate through the use of aldolase. The aldolase used in gluconeogenesis and glycolysis is a cytoplasmic protein.

Three forms of class I protein are found in vertebrates. Aldolase A is preferentially expressed in muscle and brain; aldolase B in liver, kidney, and in enterocytes; and aldolase C in brain. Aldolases A and C are mainly involved in glycolysis, while aldolase B is involved in both glycolysis and gluconeogenesis. [5] Some defects in aldolase B cause hereditary fructose intolerance. The metabolism of free fructose in liver exploits the ability of aldolase B to use fructose 1-phosphate as a substrate. [6] Archaeal fructose-bisphosphate aldolase/phosphatase is presumably involved in gluconeogenesis because its product is fructose 6-phosphate. [7]

In the Calvin cycle

The Calvin cycle is a carbon fixation pathway; it is part of photosynthesis, which convert carbon dioxide and other compounds into glucose. It and gluconeogenesis share a series of four reversible reactions. In both pathways 3-phosphoglycerate (3-PGA or 3-PG) is reduced to fructose 1,6-bisphosphate with aldolase catalyzing the last reaction. A fifth reaction, catalyzed in both pathways by fructose 1,6-bisphosphatase, hydrolyzes the fructose 1-6-bisphosphate to fructose 6-phosphate and inorganic phosphate. The large decrease in free energy makes this reaction irreversible. In the Calvin cycle aldolase also catalyzes the production of sedoheptulose 1,7-bisphosphate from DHAP and erythrose 4-phosphate. The chief products of the Calvin cycle are triose phosphate (TP), which is a mixture of DHAP and G3P, and fructose 6-phosphate. Both are also needed to regenerate RuBP. The aldolase used by plants and algae in the Calvin cycle is usually a plastid-targeted protein encoded by a nuclear gene.

Reactions

Aldolase catalyzes

fructose 1,6-bisphosphate DHAP + G3P

and also

sedoheptulose 1,7-bisphosphate DHAP + erythrose 4-phosphate
fructose 1-phosphate DHAP + glyceraldehyde

Aldolase is used in the reversible trunk of gluconeogenesis/glycolysis

2(PEP + NADH + H+ + ATP + H2O) fructose 1,6-bisphosphate + 2(NAD+ + ADP + Pi)

Aldolase is also used in the part of the Calvin cycle shared with gluconeogenesis, with the irreversible phosphate hydrolysis at the end catalyzed by fructose 1,6-bisphosphatase

2(3-PG + NADPH + H+ + ATP + H2O) fructose 1,6-bisphosphate + 2(NADP+ + ADP + Pi)
fructose 1,6-bisphosphate + H2O → fructose 6-phosphate + Pi

In gluconeogenesis 3-PG is produced by enolase and phosphoglycerate mutase acting in series

PEP + H2O 2-PG 3-PG

In the Calvin cycle 3-PG is produced by RuBisCO

RuBP + CO2 + H2O → 2(3-PG)

G3P is produced by phosphoglycerate kinase acting in series with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in gluconeogenesis, and in series with glyceraldehyde-3-phosphate dehydrogenase (NADP+) (phosphorylating) in the Calvin cycle

3-PG + ATP 1,3-bisphosphoglycerate + ADP
1,3-bisphosphoglycerate + NAD(P)H + H+ G3P + Pi + NAD(P)+

Triose-phosphate isomerase maintains DHAP and G3P in near equilibrium, producing the mixture called triose phosphate (TP)

G3P DHAP

Thus both DHAP and G3P are available to aldolase.

Moonlighting properties

Aldolase has also been implicated in many "moonlighting" or non-catalytic functions, based upon its binding affinity for many other proteins including F-actin, α-tubulin, light chain dynein, WASP, Band 3 anion exchanger, phospholipase D (PLD2), glucose transporter GLUT4, inositol trisphosphate, V-ATPase and ARNO (a guanine nucleotide exchange factor of ARF6). These associations are thought to be predominantly involved in cellular structure, however, involvement in endocytosis, parasite invasion, cytoskeleton rearrangement, cell motility, membrane protein trafficking and recycling, signal transduction and tissue compartmentalization have been explored. [8] [9] [10]

Related Research Articles

<span class="mw-page-title-main">Glycolysis</span> Catabolic pathway

Glycolysis is the metabolic pathway that converts glucose into pyruvate, and in most organisms, occurs in the liquid part of cells, the cytosol. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Fructose 1,6-bisphosphatase</span> Class of enzymes

The enzyme fructose bisphosphatase (EC 3.1.3.11; systematic name D-fructose-1,6-bisphosphate 1-phosphohydrolase) catalyses the conversion of fructose-1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis and the Calvin cycle, which are both anabolic pathways:

<span class="mw-page-title-main">Pyruvate kinase</span> Class of enzymes

Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of pyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues.

A tetrose is a monosaccharide with 4 carbon atoms. They have either an aldehyde functional group in position 1 (aldotetroses) or a ketone functional group in position 2 (ketotetroses).

<span class="mw-page-title-main">Calvin cycle</span> Light-independent reactions in photosynthesis

The Calvin cycle,light-independent reactions, bio synthetic phase,dark reactions, or photosynthetic carbon reduction (PCR) cycle of photosynthesis is a series of chemical reactions that convert carbon dioxide and hydrogen-carrier compounds into glucose. The Calvin cycle is present in all photosynthetic eukaryotes and also many photosynthetic bacteria. In plants, these reactions occur in the stroma, the fluid-filled region of a chloroplast outside the thylakoid membranes. These reactions take the products of light-dependent reactions and perform further chemical processes on them. The Calvin cycle uses the chemical energy of ATP and reducing power of NADPH from the light dependent reactions to produce sugars for the plant to use. These substrates are used in a series of reduction-oxidation reactions to produce sugars in a step-wise process; there is no direct reaction that converts several molecules of CO2 to a sugar. There are three phases to the light-independent reactions, collectively called the Calvin cycle: carboxylation, reduction reactions, and ribulose 1,5-bisphosphate (RuBP) regeneration.

<span class="mw-page-title-main">Glyceraldehyde 3-phosphate</span> Chemical compound

Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms. With the chemical formula H(O)CCH(OH)CH2OPO32-, this anion is a monophosphate ester of glyceraldehyde.

<span class="mw-page-title-main">Aldolase A</span> Mammalian protein found in Homo sapiens

Aldolase A, also known as fructose-bisphosphate aldolase, is an enzyme that in humans is encoded by the ALDOA gene on chromosome 16.

Dihydroxyacetone phosphate (DHAP, also glycerone phosphate in older texts) is the anion with the formula HOCH2C(O)CH2OPO32-. This anion is involved in many metabolic pathways, including the Calvin cycle in plants and glycolysis. It is the phosphate ester of dihydroxyacetone.

<span class="mw-page-title-main">3-Phosphoglyceric acid</span> Chemical compound

3-Phosphoglyceric acid (3PG, 3-PGA, or PGA) is the conjugate acid of 3-phosphoglycerate or glycerate 3-phosphate (GP or G3P). This glycerate is a biochemically significant metabolic intermediate in both glycolysis and the Calvin-Benson cycle. The anion is often termed as PGA when referring to the Calvin-Benson cycle. In the Calvin-Benson cycle, 3-phosphoglycerate is typically the product of the spontaneous scission of an unstable 6-carbon intermediate formed upon CO2 fixation. Thus, two equivalents of 3-phosphoglycerate are produced for each molecule of CO2 that is fixed. In glycolysis, 3-phosphoglycerate is an intermediate following the dephosphorylation (reduction) of 1,3-bisphosphoglycerate.

<span class="mw-page-title-main">Fructose 1,6-bisphosphate</span> Chemical compound

Fructose 1,6-bisphosphate, also known as Harden-Young ester, is fructose sugar phosphorylated on carbons 1 and 6. The β-D-form of this compound is common in cells. Upon entering the cell, most glucose and fructose is converted to fructose 1,6-bisphosphate.

<span class="mw-page-title-main">Aldolase B</span> Mammalian protein found in Homo sapiens

Aldolase B also known as fructose-bisphosphate aldolase B or liver-type aldolase is one of three isoenzymes of the class I fructose 1,6-bisphosphate aldolase enzyme, and plays a key role in both glycolysis and gluconeogenesis. The generic fructose 1,6-bisphosphate aldolase enzyme catalyzes the reversible cleavage of fructose 1,6-bisphosphate (FBP) into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (DHAP) as well as the reversible cleavage of fructose 1-phosphate (F1P) into glyceraldehyde and dihydroxyacetone phosphate. In mammals, aldolase B is preferentially expressed in the liver, while aldolase A is expressed in muscle and erythrocytes and aldolase C is expressed in the brain. Slight differences in isozyme structure result in different activities for the two substrate molecules: FBP and fructose 1-phosphate. Aldolase B exhibits no preference and thus catalyzes both reactions, while aldolases A and C prefer FBP.

A futile cycle, also known as a substrate cycle, occurs when two metabolic pathways run simultaneously in opposite directions and have no overall effect other than to dissipate energy in the form of heat. The reason this cycle was called "futile" cycle was because it appeared that this cycle operated with no net utility for the organism. As such, it was thought of being a quirk of the metabolism and thus named a futile cycle. After further investigation it was seen that futile cycles are very important for regulating the concentrations of metabolites. For example, if glycolysis and gluconeogenesis were to be active at the same time, glucose would be converted to pyruvate by glycolysis and then converted back to glucose by gluconeogenesis, with an overall consumption of ATP. Futile cycles may have a role in metabolic regulation, where a futile cycle would be a system oscillating between two states and very sensitive to small changes in the activity of any of the enzymes involved. The cycle does generate heat, and may be used to maintain thermal homeostasis, for example in the brown adipose tissue of young mammals, or to generate heat rapidly, for example in insect flight muscles and in hibernating animals during periodical arousal from torpor. It has been reported that the glucose metabolism substrate cycle is not a futile cycle but a regulatory process. For example, when energy is suddenly needed, ATP is replaced by AMP, a much more reactive adenine.

<span class="mw-page-title-main">Fructose 2,6-bisphosphate</span> Chemical compound

Fructose 2,6-bisphosphate, abbreviated Fru-2,6-P2, is a metabolite that allosterically affects the activity of the enzymes phosphofructokinase 1 (PFK-1) and fructose 1,6-bisphosphatase (FBPase-1) to regulate glycolysis and gluconeogenesis. Fru-2,6-P2 itself is synthesized and broken down by the bifunctional enzyme phosphofructokinase 2/fructose-2,6-bisphosphatase (PFK-2/FBPase-2).

Glucose-1,6-bisphosphate synthase is a type of enzyme called a phosphotransferase and is involved in mammalian starch and sucrose metabolism. It catalyzes the transfer of a phosphate group from 1,3-bisphosphoglycerate to glucose-1-phosphate, yielding 3-phosphoglycerate and glucose-1,6-bisphosphate.

<span class="mw-page-title-main">Fructose 1-phosphate</span> Chemical compound

Fructose-1-phosphate is a derivative of fructose. It is generated mainly by hepatic fructokinase but is also generated in smaller amounts in the small intestinal mucosa and proximal epithelium of the renal tubule. It is an important intermediate of glucose metabolism. Because fructokinase has a high Vmax fructose entering cells is quickly phosphorylated to fructose 1-phosphate. In this form it is usually accumulated in the liver until it undergoes further conversion by aldolase B.

The enzyme methylglyoxal synthase catalyzes the chemical reaction

<span class="mw-page-title-main">Aldolase C</span> Protein-coding gene in the species Homo sapiens

Aldolase C, fructose-bisphosphate, is an enzyme that, in humans, is encoded by the ALDOC gene on chromosome 17. This gene encodes a member of the class I fructose-bisphosphate aldolase gene family. Expressed specifically in the hippocampus and Purkinje cells of the brain, the encoded protein is a glycolytic enzyme that catalyzes the reversible aldol cleavage of fructose 1,6-bisphosphate and fructose-1-phosphate to dihydroxyacetone phosphate and either glyceraldehyde 3-phosphate or glyceraldehyde, respectively.[provided by RefSeq, Jul 2008]

Fructolysis refers to the metabolism of fructose from dietary sources. Though the metabolism of glucose through glycolysis uses many of the same enzymes and intermediate structures as those in fructolysis, the two sugars have very different metabolic fates in human metabolism. Unlike glucose, which is directly metabolized widely in the body, fructose is almost entirely metabolized in the liver in humans, where it is directed toward replenishment of liver glycogen and triglyceride synthesis. Under one percent of ingested fructose is directly converted to plasma triglyceride. 29% - 54% of fructose is converted in liver to glucose, and about a quarter of fructose is converted to lactate. 15% - 18% is converted to glycogen. Glucose and lactate are then used normally as energy to fuel cells all over the body.

Bisphosphate may refer to:

References

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  2. Patron NJ, Rogers MB, Keeling PJ (2004). "Gene replacement of fructose-1,6-bisphosphate aldolase supports the hypothesis of a single photosynthetic ancestor of chromalveolates". Eukaryotic Cell. 3 (5): 1169–75. doi:10.1128/EC.3.5.1169-1175.2004. PMC   522617 . PMID   15470245.
  3. Trung Hieu Pham, Shreesha Rao, Ta-Chih Cheng, Pei-Chi Wang, Shih-Chu Chen, The moonlighting protein fructose 1,6-bisphosphate aldolase as a potential vaccine candidate against Photobacterium damselae subsp. piscicida in Asian sea bass (Lates calcarifer), Developmental & Comparative Immunology,Volume 124,2021,104187,ISSN 0145-305X,https://doi.org/10.1016/j.dci.2021.104187.
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  5. Walther EU, Dichgans M, Maricich SM, Romito RR, Yang F, Dziennis S, Zackson S, Hawkes R, Herrup K (1998). "Genomic sequences of aldolase C (Zebrin II) direct lacZ expression exclusively in non-neuronal cells of transgenic mice". Proc. Natl. Acad. Sci. U.S.A. 95 (5): 2615–20. Bibcode:1998PNAS...95.2615W. doi: 10.1073/pnas.95.5.2615 . PMC   19434 . PMID   9482935.
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  8. Rangarajan ES, Park H, Fortin E, Sygusch J, Izard T (2010). "Mechanism of Alolase Control of Sorting Nexin 9 Function in Endocytosis". J. Biol. Chem. 285 (16): 11983–90. doi: 10.1074/jbc.M109.092049 . PMC   2852936 . PMID   20129922.
  9. Ahn AH, Dziennis S, Hawkes R, Herrup K (1994). "The cloning of zebrin II reveals its identity with aldolase C". Development. 120 (8): 2081–90. doi:10.1242/dev.120.8.2081. PMID   7925012.
  10. Merkulova M, Hurtado-Lorenzo A, Hosokawa H, Zhuang Z, Brown D, Ausiello DA, Marshansky V (2011). "Aldolase directly interacts with ARNO and modulates cell morphology and acid vesicle distribution". Am J Physiol Cell Physiol. 300 (6): C1442-55. doi:10.1152/ajpcell.00076.2010. PMC   3118619 . PMID   21307348.

Further reading