Ribose-5-phosphate isomerase

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ribose-5-phosphate isomerase
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D-Ribose-5-phosphate isomerase homotetramer, Pyrococcus horikoshii
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EC no. 5.3.1.6
CAS no. 9023-83-0
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Ribose-5-phosphate isomerase (Rpi) encoded by the RPIA gene is an enzyme (EC 5.3.1.6) that catalyzes the conversion between ribose-5-phosphate (R5P) and ribulose-5-phosphate (Ru5P). It is a member of a larger class of isomerases which catalyze the interconversion of chemical isomers (in this case structural isomers of pentose). It plays a vital role in biochemical metabolism in both the pentose phosphate pathway and the Calvin cycle. The systematic name of this enzyme class is D-ribose-5-phosphate aldose-ketose-isomerase.

Contents

Structure

Gene

RpiA in human beings is encoded on the second chromosome on the short arm (p arm) at position 11.2. Its encoding sequence is nearly 60,000 base pairs long. [1] The only known naturally occurring genetic mutation results in ribose-5-phosphate isomerase deficiency, discussed below. The enzyme is thought to have been present for most of evolutionary history. Knock-out experiments conducted on the genes of various species meant to encode RpiA have indicated similar conserved residues and structural motifs, indicating ancient origins of the gene. [2]

Protein

A structural diagram of the enzyme ribose-5-phosphate isomerase by Zhang, et al. Ribose-5-phosphate isomerase.png
A structural diagram of the enzyme ribose-5-phosphate isomerase by Zhang, et al.

Rpi exists as two distinct proteins, termed RpiA and RpiB. Although RpiA and RpiB catalyze the same reaction, they show no sequence or overall structural homology. According to Jung et al., [3] an assessment of RpiA using SDS-PAGE shows that the enzyme is a homodimer of 25 kDa subunits. The molecular mass of the RpiA dimer was found to be 49 kDa [3] by gel filtration. Recently, the crystal structure of RpiA was determined. (please see http://www3.interscience.wiley.com/cgi-bin/fulltext/97516673/PDFSTAR%5B%5D)

Due to its role in the pentose phosphate pathway and the Calvin cycle, RpiA is highly conserved in most organisms, such as bacteria, plants, and animals. RpiA plays an essential role in the metabolism of plants and animals, as it is involved in the Calvin cycle which takes place in plants, and the pentose phosphate pathway which takes place in plants as well as animals.

All orthologs of the enzyme maintain an asymmetric tetramer quaternary structure with a cleft containing the active site. Each subunit consists of a five stranded β-sheet. These β-sheets are surrounded on both sides by α-helices. [4] This αβα motif is not uncommon in other proteins, suggesting possible homology with other enzymes. [5] The separate molecules of the enzyme are held together by highly polar contacts on the external surfaces of the monomers. It is presumed that the active site is located where multiple β-sheet C termini come together in the enzymatic cleft. This cleft is capable of closing upon recognition of the phosphate on the pentose (or an appropriate phosphate inhibitor). The active site is known to contain conserved residues equivalent to the E. coli residues Asp81, Asp84, and Lys94. These are directly involved in catalysis. [6]

Mechanism

In the reaction, the overall consequence is the movement of a carbonyl group from carbon number 1 to carbon number 2; this is achieved by the reaction going through an enediol intermediate (Figure 1). [6] Through site-directed mutagenesis, Asp87 of spinach RpiA was suggested to play the role of a general base in the interconversion of R5P to Ru5P. [7]

Mech 2.png

The first step in the catalysis is the docking of the pentose into the active site in the enzymatic cleft, followed by allosteric closing of the cleft. The enzyme is capable of bonding with the open-chain or ring form of the sugar-phosphate. If it does bind the furanose ring, it next opens the ring. Then the enzyme forms the eneldiol which is stabilized by a lysine or arginine residue. [6] [8] Calculations have demonstrated that this stabilization is the most significant contributor to the overall catalytic activity of this isomerase and a number of others like it. [9]

Function

The protein encoded by RPIA gene is an enzyme, which catalyzes the reversible conversion between ribose-5-phosphate and ribulose-5-phosphate in the pentose-phosphate pathway. This gene is highly conserved in most organisms. The enzyme plays an essential role in the carbohydrate metabolism. Mutations in this gene cause ribose 5-phosphate isomerase deficiency. A pseudogene is found on chromosome 18. [10]

Pentose phosphate pathway

In the non-oxidative part of the pentose phosphate pathway, RPIA converts Ru5P to R5P which then is converted by ribulose-phosphate 3-epimerase to xylulose-5-phosphate (figure 3). [11] The result of the reaction essentially is the conversion of the pentose phosphates to intermediates used in the glycolytic pathway. In the oxidative part of the pentose phosphate pathway, RpiA converts Ru5P to the final product, R5P through the isomerization reaction (figure 3). The oxidative branch of the pathway is a major source for NADPH which is needed for biosynthetic reactions and protection against reactive oxygen species. [12]

Final- calvin and PPP.JPG

Calvin cycle

In the Calvin cycle, the energy from the electron carriers is used in carbon fixation, the conversion of carbon dioxide and water into carbohydrates. RPIA is essential in the cycle, as Ru5P generated from R5P is subsequently converted to ribulose-1,5-bisphosphate (RuBP), the acceptor of carbon dioxide in the first dark reaction of photosynthesis (Figure 3). [13] The direct product of RuBP carboxylase reaction is glyceraldehyde-3-phosphate; these are subsequently used to make larger carbohydrates. [14] Glyceraldehyde-3-phosphate is converted to glucose which is later converted by the plant to storage forms (e.g., starch or cellulose) or used for energy. [15]

Clinical significance

Ribose-5-phosphate isomerase deficiency is mutated in a rare disorder, Ribose-5-phosphate isomerase deficiency. The disease has only one known affected patient, diagnosed in 1999. [16] It has been found to be caused by a combination of two mutations. The first is an insertion of a premature stop codon into the gene encoding the isomerase, and the second is a missense mutation. The molecular pathology is, as yet, unclear. [17]

RpiA and hepatocarcinogenesis

Human ribose-5-phosphate isomerase A (RpiA) plays a role in human hepatocellular carcinoma (HCC). [18] A significant increase in RpiA expression was detected both in tumor biopsies of HCC patients and in a liver cancer tissue array. Importantly, the clinicopathological analysis indicated that RpiA mRNA levels were highly correlated with clinical stage, grade, tumor size, types, invasion and alpha-fetoprotein levels in the HCC patients. In addition, the ability of RpiA to regulate cell proliferation and colony formation in different liver cancer cell lines required ERK signaling as well as the negative modulation of PP2A activity and that the effects of RpiA could be modulated by the addition of either a PP2A inhibitor or activator. It suggests that RpiA overexpression can induce oncogenesis in HCC. [19]

RpiA and the malaria parasite

RpiA generated attention when the enzyme was found to play an essential role in the pathogenesis of the parasite Plasmodium falciparum, the causative agent of malaria. Plasmodium cells have a critical need for a large supply of the reducing power of NADPH via PPP in order to support their rapid growth. The need for NADPH is also required to detoxify heme, the product of hemoglobin degradation. [20] Furthermore, Plasmodium has an intense requirement for nucleic acid production to support its rapid proliferation. The R5P produced via increased pentose phosphate pathway activity is used to generate 5-phospho-D-ribose α-1-pyrophosphate (PRPP) needed for nucleic acid synthesis. It has been shown that PRPP concentrations are increased 56 fold in infected erythrocytes compared with uninfected erythrocytes. [17] Hence, designing drugs that target RpiA in Plasmodium falciparum could have therapeutic potential for patients that suffer from malaria.

Interactions

RPIA has been shown to interact with PP2A. [19]

Structural studies

As of late 2007, 15 structures have been solved for this class of enzymes, with PDB accession codes 1LK5, 1LK7, 1LKZ, 1M0S, 1NN4, 1O1X, 1O8B, 1UJ4, 1UJ5, 1UJ6, 1USL, 1XTZ, 2BES, 2BET, and 2F8M.

Related Research Articles

<span class="mw-page-title-main">Glucose 6-phosphate</span> Chemical compound

Glucose 6-phosphate is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this way.

<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 (redox) 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">Pentose phosphate pathway</span> Series of interconnected biochemical reactions

The pentose phosphate pathway is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses as well as ribose 5-phosphate, a precursor for the synthesis of nucleotides. While the pentose phosphate pathway does involve oxidation of glucose, its primary role is anabolic rather than catabolic. The pathway is especially important in red blood cells (erythrocytes). The reactions of the pathway were elucidated in the early 1950s by Bernard Horecker and co-workers.

<span class="mw-page-title-main">Ribulose</span> Monosaccharide with five carbon atoms and a ketone functional group

Ribulose is a ketopentose — a monosaccharide containing five carbon atoms, and including a ketone functional group. It has chemical formula C5H10O5. Two enantiomers are possible, d-ribulose and l-ribulose. d-Ribulose is the diastereomer of d-xylulose.

<span class="mw-page-title-main">Glucose-6-phosphate isomerase</span> Mammalian protein found in Homo sapiens

Glucose-6-phosphate isomerase (GPI), alternatively known as phosphoglucose isomerase/phosphoglucoisomerase (PGI) or phosphohexose isomerase (PHI), is an enzyme that in humans is encoded by the GPI gene on chromosome 19. This gene encodes a member of the glucose phosphate isomerase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as a glycolytic enzyme that interconverts glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P). Extracellularly, the encoded protein functions as a neurotrophic factor that promotes survival of skeletal motor neurons and sensory neurons, and as a lymphokine that induces immunoglobulin secretion. The encoded protein is also referred to as autocrine motility factor (AMF) based on an additional function as a tumor-secreted cytokine and angiogenic factor. Defects in this gene are the cause of nonspherocytic hemolytic anemia, and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

<span class="mw-page-title-main">Transketolase</span> Enzyme involved in metabolic pathways

Transketolase is an enzyme that, in humans, is encoded by the TKT gene. It participates in both the pentose phosphate pathway in all organisms and the Calvin cycle of photosynthesis. Transketolase catalyzes two important reactions, which operate in opposite directions in these two pathways. In the first reaction of the non-oxidative pentose phosphate pathway, the cofactor thiamine diphosphate accepts a 2-carbon fragment from a 5-carbon ketose (D-xylulose-5-P), then transfers this fragment to a 5-carbon aldose (D-ribose-5-P) to form a 7-carbon ketose (sedoheptulose-7-P). The abstraction of two carbons from D-xylulose-5-P yields the 3-carbon aldose glyceraldehyde-3-P. In the Calvin cycle, transketolase catalyzes the reverse reaction, the conversion of sedoheptulose-7-P and glyceraldehyde-3-P to pentoses, the aldose D-ribose-5-P and the ketose D-xylulose-5-P.

<span class="mw-page-title-main">6-Phosphogluconate dehydrogenase</span> Class of enzymes

6-Phosphogluconate dehydrogenase (6PGD) is an enzyme in the pentose phosphate pathway. It forms ribulose 5-phosphate from 6-phosphogluconate:

<span class="mw-page-title-main">Ribulose 5-phosphate</span> Chemical compound

Ribulose 5-phosphate is one of the end-products of the pentose phosphate pathway. It is also an intermediate in the Calvin cycle.

<span class="mw-page-title-main">Transaldolase</span> Enzyme family

Transaldolase is an enzyme of the non-oxidative phase of the pentose phosphate pathway. In humans, transaldolase is encoded by the TALDO1 gene.

<span class="mw-page-title-main">Ribose 5-phosphate</span> Chemical compound

Ribose 5-phosphate (R5P) is both a product and an intermediate of the pentose phosphate pathway. The last step of the oxidative reactions in the pentose phosphate pathway is the production of ribulose 5-phosphate. Depending on the body's state, ribulose 5-phosphate can reversibly isomerize to ribose 5-phosphate. Ribulose 5-phosphate can alternatively undergo a series of isomerizations as well as transaldolations and transketolations that result in the production of other pentose phosphates as well as fructose 6-phosphate and glyceraldehyde 3-phosphate.

<span class="mw-page-title-main">Phosphopentose epimerase</span> Class of enzymes

Phosphopentose epimerase encoded in humans by the RPE gene is a metalloprotein that catalyzes the interconversion between D-ribulose 5-phosphate and D-xylulose 5-phosphate.

<span class="mw-page-title-main">6-phosphogluconolactonase</span> Cytosolic enzyme

6-Phosphogluconolactonase (EC 3.1.1.31, 6PGL, PGLS, systematic name 6-phospho-D-glucono-1,5-lactone lactonohydrolase) is a cytosolic enzyme found in all organisms that catalyzes the hydrolysis of 6-phosphogluconolactone to 6-phosphogluconic acid in the oxidative phase of the pentose phosphate pathway:

<span class="mw-page-title-main">Xylose metabolism</span>

D-Xylose is a five-carbon aldose that can be catabolized or metabolized into useful products by a variety of organisms.

<span class="mw-page-title-main">L-ribulose-5-phosphate 4-epimerase</span>

In enzymology, a L-ribulose-5-phosphate 4-epimerase is an enzyme that catalyzes the interconversion of ribulose 5-phosphate and xylulose 5-phosphate in the oxidative phase of the Pentose phosphate pathway.

<span class="mw-page-title-main">Phosphoribulokinase</span>

Phosphoribulokinase (PRK) (EC 2.7.1.19) is an essential photosynthetic enzyme that catalyzes the ATP-dependent phosphorylation of ribulose 5-phosphate (RuP) into ribulose 1,5-bisphosphate (RuBP), both intermediates in the Calvin Cycle. Its main function is to regenerate RuBP, which is the initial substrate and CO2-acceptor molecule of the Calvin Cycle. PRK belongs to the family of transferase enzymes, specifically those transferring phosphorus-containing groups (phosphotransferases) to an alcohol group acceptor. Along with ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCo), phosphoribulokinase is unique to the Calvin Cycle. Therefore, PRK activity often determines the metabolic rate in organisms for which carbon fixation is key to survival. Much initial work on PRK was done with spinach leaf extracts in the 1950s; subsequent studies of PRK in other photosynthetic prokaryotic and eukaryotic organisms have followed. The possibility that PRK might exist was first recognized by Weissbach et al. in 1954; for example, the group noted that carbon dioxide fixation in crude spinach extracts was enhanced by the addition of ATP. The first purification of PRK was conducted by Hurwitz and colleagues in 1956.

ATP + Mg2+ - D-ribulose 5-phosphate  ADP + D-ribulose 1,5-bisphosphate
<span class="mw-page-title-main">RPE (gene)</span> Protein-coding gene in the species Homo sapiens

Ribulose-phosphate 3-epimerase is an enzyme that in humans is encoded by the RPE gene.

<span class="mw-page-title-main">TPI1</span> Protein-coding gene in the species Homo sapiens

Triosephosphate isomerase is an enzyme that in humans is encoded by the TPI1 gene.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

Ribose-5-phosphate isomerase deficiency (RPID) is a rare human disorder caused by mutations in ribose-5-phosphate isomerase, an enzyme of the pentose phosphate pathway. With only four diagnosed patients over a 27-year period, RPI deficiency is the second rarest disease known as of now, being beaten only by Fields Condition affecting two known individuals, Catherine and Kirstie Fields.

References

  1. ↑ U.S. National Library of Medicine http://ghr.nlm.nih.gov/gene/RPIA
  2. ↑ Sørensen KI, Hove-Jensen B (February 1996). "Ribose catabolism of Escherichia coli: characterization of the rpiB gene encoding ribose phosphate isomerase B and of the rpiR gene, which is involved in regulation of rpiB expression". Journal of Bacteriology. 178 (4): 1003–11. doi:10.1128/jb.178.4.1003-1011.1996. PMC   177759 . PMID   8576032.
  3. 1 2 Jung CH, Hartman FC, Lu TY, Larimer FW (January 2000). "D-ribose-5-phosphate isomerase from spinach: heterologous overexpression, purification, characterization, and site-directed mutagenesis of the recombinant enzyme". Archives of Biochemistry and Biophysics. 373 (2): 409–17. doi:10.1006/abbi.1999.1554. PMID   10620366. S2CID   13217828.
  4. ↑ Zhang RG, Andersson CE, Skarina T, Evdokimova E, Edwards AM, Joachimiak A, Savchenko A, Mowbray SL (October 2003). "The 2.2 Å resolution structure of RpiB/AlsB from Escherichia coli illustrates a new approach to the ribose-5-phosphate isomerase reaction". Journal of Molecular Biology. 332 (5): 1083–94. doi:10.1016/j.jmb.2003.08.009. PMC   2792017 . PMID   14499611.
  5. ↑ Rossmann MG, Moras D, Olsen KW (July 1974). "Chemical and biological evolution of nucleotide-binding protein". Nature. 250 (463): 194–9. Bibcode:1974Natur.250..194R. doi:10.1038/250194a0. PMID   4368490. S2CID   4273028.
  6. 1 2 3 Zhang Rg, Andersson CE, Savchenko A, Skarina T, Evdokimova E, Beasley S, Arrowsmith CH, Edwards AM, Joachimiak A, Mowbray SL (January 2003). "Structure of Escherichia coli ribose-5-phosphate isomerase: a ubiquitous enzyme of the pentose phosphate pathway and the Calvin cycle". Structure. 11 (1): 31–42. doi:10.1016/S0969-2126(02)00933-4. PMC   2792023 . PMID   12517338.
  7. ↑ Gengenbacher M, Fitzpatrick TB, Raschle T, Flicker K, Sinning I, Müller S, Macheroux P, Tews I, Kappes B (February 2006). "Vitamin B6 biosynthesis by the malaria parasite Plasmodium falciparum: biochemical and structural insights". The Journal of Biological Chemistry. 281 (6): 3633–41. doi: 10.1074/jbc.M508696200 . PMID   16339145.
  8. ↑ Woodruff, William W.; Wolfenden, Richard (18 July 1978). "Inhibition of ribose-5-phosphate by 4-phosphoerythronate". Journal of Biological Chemistry. 254 (13). Retrieved 6 March 2013.
  9. ↑ Feierberg I, Åqvist (2002). "Computational modeling of enzymatic keto–enol isomerization reactions". Theoretical Chemistry Accounts. 108 (2): 71–84. doi:10.1007/s00214-002-0365-7. S2CID   95097042.
  10. ↑ "Entrez Gene: RPIA ribose 5-phosphate isomerase A".
  11. ↑ Berg, Jeremy M. (2012). Biochemistry. New York: W.H. Freeman and Company. ISBN   978-1-4292-2936-4.
  12. ↑ Struzyńska L, Chalimoniuk M, Sulkowski G (September 2005). "The role of astroglia in Pb-exposed adult rat brain with respect to glutamate toxicity". Toxicology. 212 (2–3): 185–94. doi:10.1016/j.tox.2005.04.013. PMID   15955607.
  13. ↑ Martin W, Henze K, Kellerman J, Flechner A, Schnarrenberger C (February 1996). "Microsequencing and cDNA cloning of the Calvin cycle/OPPP enzyme ribose-5-phosphate isomerase (EC 5.3.1.6) from spinach chloroplasts". Plant Molecular Biology. 30 (4): 795–805. doi:10.1007/BF00019012. PMID   8624410. S2CID   4218453.
  14. ↑ A. A. Benson; J. A. Bassham; M. Calvin; T. C. Goodale; V. A. Haas; W. Stepka (1950). "The Path of Carbon in Photosynthesis. V. Paper Chromatography and Radioautography of the Products1". Journal of the American Chemical Society. 72 (4): 1710–1718. doi:10.1021/ja01160a080.
  15. ↑ Nelson, David L. (2005). Principles of Biochemistry . New Yord: W.H Freeman and Company. ISBN   0-7167-4339-6.
  16. 1 2 Huck JH, Verhoeven NM, Struys EA, Salomons GS, Jakobs C, van der Knaap MS (April 2004). "Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy". American Journal of Human Genetics. 74 (4): 745–51. doi:10.1086/383204. PMC   1181951 . PMID   14988808.
  17. ↑ Riganti C, Gazzano E, Polimeni M, Aldieri E, Ghigo D (August 2012). "The pentose phosphate pathway: an antioxidant defense and a crossroad in tumor cell fate". Free Radical Biology & Medicine. 53 (3): 421–36. doi:10.1016/j.freeradbiomed.2012.05.006. PMID   22580150.
  18. 1 2 Ciou SC, Chou YT, Liu YL, Nieh YC, Lu JW, Huang SF, Chou YT, Cheng LH, Lo JF, Chen MJ, Yang MC, Yuh CH, Wang HD (July 2015). "Ribose-5-phosphate isomerase A regulates hepatocarcinogenesis via PP2A and ERK signaling". International Journal of Cancer. 137 (1): 104–15. doi: 10.1002/ijc.29361 . PMID   25429733.
  19. ↑ Becker K, Rahlfs S, Nickel C, Schirmer RH (April 2003). "Glutathione--functions and metabolism in the malarial parasite Plasmodium falciparum". Biological Chemistry. 384 (4): 551–66. doi:10.1515/BC.2003.063. PMID   12751785. S2CID   20083367.
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