4-Amino-5-hydroxymethyl-2-methylpyrimidine

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4-Amino-5-hydroxymethyl-2-methylpyrimidine
Toxopyrimidine.svg
Toxopyrimidine 3D structure.png
Names
Preferred IUPAC name
(4-Amino-2-methylpyrimidin-5-yl)methanol
Other names
HMP
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
PubChem CID
UNII
  • HMP:InChI=1S/C6H9N3O/c1-4-8-2-5(3-10)6(7)9-4/h2,10H,3H2,1H3,(H2,7,8,9)
    Key: VUTBELPREDJDDH-UHFFFAOYSA-N
  • HMP-P:InChI=1S/C6H10N3O4P/c1-4-8-2-5(6(7)9-4)3-13-14(10,11)12/h2H,3H2,1H3,(H2,7,8,9)(H2,10,11,12)/p-1
    Key: PKYFHKIYHBRTPI-UHFFFAOYSA-M
  • HMP-PP:InChI=1S/C6H11N3O7P2/c1-4-8-2-5(6(7)9-4)3-15-18(13,14)16-17(10,11)12/h2H,3H2,1H3,(H,13,14)(H2,7,8,9)(H2,10,11,12)/p-2
    Key: AGQJQCFEPUVXNK-UHFFFAOYSA-L
  • HMP:CC1=NC=C(C(=N1)N)CO
  • HMP-P:CC1=NC=C(C(=N1)N)COP(=O)(O)[O-]
  • HMP-PP:CC1=NC=C(C(=N1)N)COP(=O)([O-])OP(=O)(O)[O-]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Within the field of biochemistry, 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP) also known as toxopyrimidine together with its mono phosphate (HMP-P) and pyrophosphate (HMP-PP) esters are biogenetic precursors to the important biochemical cofactor thiamine pyrophosphate (TPP), a derivative of thiamine (vitamin B1).

Contents

HMP, HMP-P and HMP-PP are found along with thiamine forms in a wide variety of living organisms. Thiamine in various salt, formulation and biological matrix forms are used to supplement human and animal diets because these organisms lack the capability to produce it. Methodologies are being sought for biotechnology-based production of thiamine forms and for increasing thiamine content in food sources.

TPP biogenesis

In microorganisms and plants TPP results from coupling of pyrimidine fragment HMP-PP with thiazole fragment HET-P to give thiamine monophosphate, followed by conversion to the pyrophosphate. [1] [2]

Biogenesis of HMP-P and HET-P vary with types of organism.

HMP-P biogenesis

In bacteria, HMP-P arises by conversion of the purine biosynthetic precursor 5-aminoimidazole ribotide (AIR) through the action of enzymes such as phosphomethylpyrimidine synthase, a member of the radical SAM superfamily. [3] [4] Studies using isotopically labelled AIR have shown which atoms carry into the product. [5] [6] Mechanisms by which this occurs are not yet known with certainty.

In yeasts, HMP-P is derived from metabolites of histidine and pyridoxine. [7] [8] Some of these transformations appear to be catalyzed by radical SAM enzymes. Isotopically labelled precursors have been used to investigate this biogenesis. [5] [9] [10] Mechanisms of the transformations are unknown.

In Salmonella , HMP-P can be derived independently of purine biogenesis when AICAR is available. [11] [12]

In algae, thiamine forms and precursors are scavenged by uptake from water of exogenous products from other organisms. In higher plants, thiamine biogenesis resembles that of bacteria. [2] [13] In some circumstances, thiamine forms and precursors may be obtained through symbiotic relationships with microorganisms in the soil.

Genes relevant for transformations in the biogenesis of HMP-P, HET-P, and TPP have been identified in various organisms and some of the proteins resulting from their expression have been characterized. [14] [15] Biosynthesis of TPP is feedback inhibited through actions of a riboswitch. [16]

Research is ongoing towards understanding biochemistry involved and towards facilitating technologies of socioeconomic value for supply of thiamine in various forms.

Commercially available salts thiamine chloride and thiamine nitrate are produced at scales of thousands of tons annually by chemistry-based manufacturing processes in Europe and Asia. [17] [18] These salts are supplied for formulations for supplementation of human diet and as feed additives for cattle, swine, poultry and fish.

Research for potential biotechnology-based production of thiamine [19] [20] [21] has resulted in patent applications claiming fermentation using recombinant microorganisms modified to deregulate feedback inhibition and allow release of thiamine forms to the media as demonstrated at small scale. [22] [23]

Thiamine forms and their bio-precursors are produced at very large scale in biological matrices such as yeast, grains, plants and meats widely consumed as food and feed. Research into genetic modification of plants. [24] has led to higher levels of thiamine in foodstuffs, such as rice. [25] Use of thiamine forms and their bio-precursors by various means such as seed coating or soil and foliar fertilization to improve plant growth and properties are being investigated. [26]

Related Research Articles

<span class="mw-page-title-main">Nucleotide</span> Biological molecules constituting nucleic acids

Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

<span class="mw-page-title-main">Thiamine</span> Chemical compound

Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient for humans and animals. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thiamine are required for some metabolic reactions, including the breakdown of glucose and amino acids.

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

In molecular biology, a riboswitch is a regulatory segment of a messenger RNA molecule that binds a small molecule, resulting in a change in production of the proteins encoded by the mRNA. Thus, an mRNA that contains a riboswitch is directly involved in regulating its own activity, in response to the concentrations of its effector molecule. The discovery that modern organisms use RNA to bind small molecules, and discriminate against closely related analogs, expanded the known natural capabilities of RNA beyond its ability to code for proteins, catalyze reactions, or to bind other RNA or protein macromolecules.

<span class="mw-page-title-main">Thiamine pyrophosphate</span> Chemical compound

Thiamine pyrophosphate (TPP or ThPP), or thiamine diphosphate (ThDP), or cocarboxylase is a thiamine (vitamin B1) derivative which is produced by the enzyme thiamine diphosphokinase. Thiamine pyrophosphate is a cofactor that is present in all living systems, in which it catalyzes several biochemical reactions.

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

Thiaminase is an enzyme that metabolizes or breaks down thiamine into pyrimidine and thiazole. It is an antinutrient when consumed.

<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">Phosphoribosyl pyrophosphate</span> Chemical compound

Phosphoribosyl pyrophosphate (PRPP) is a pentose phosphate. It is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, as well as in pyrimidine nucleotide formation. Hence it is a building block for DNA and RNA. The vitamins thiamine and cobalamin, and the amino acid tryptophan also contain fragments derived from PRPP. It is formed from ribose 5-phosphate (R5P) by the enzyme ribose-phosphate diphosphokinase:

<span class="mw-page-title-main">Thiamine triphosphate</span> Chemical compound

Thiamine triphosphate (ThTP) is a biomolecule found in most organisms including bacteria, fungi, plants and animals. Chemically, it is the triphosphate derivative of the vitamin thiamine.

<span class="mw-page-title-main">Benfotiamine</span> Thiamine analogue

Benfotiamine is a synthetic, fat-soluble, S-acyl derivative of thiamine that is approved in some countries as a medication or dietary supplement to treat diabetic sensorimotor polyneuropathy. Benfotiamine was developed in late 1950s in Japan.

<span class="mw-page-title-main">Phosphoribosylamine</span> Chemical compound

Phosphoribosylamine (PRA) is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, and hence is a building block for DNA and RNA. The vitamins thiamine and cobalamin also contain fragments derived from PRA.

<span class="mw-page-title-main">Phosphoribosyl-N-formylglycineamide</span> Chemical compound

Phosphoribosyl-N-formylglycineamide is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, and hence is a building block for DNA and RNA. The vitamins thiamine and cobalamin also contain fragments derived from FGAR.

<span class="mw-page-title-main">TPP riboswitch</span> RNA secondary structure

The TPP riboswitch, also known as the THI element and Thi-box riboswitch, is a highly conserved RNA secondary structure. It serves as a riboswitch that binds thiamine pyrophosphate (TPP) directly and modulates gene expression through a variety of mechanisms in archaea, bacteria and eukaryotes. TPP is the active form of thiamine (vitamin B1), an essential coenzyme synthesised by coupling of pyrimidine and thiazole moieties in bacteria. The THI element is an extension of a previously detected thiamin-regulatory element, the thi box, there is considerable variability in the predicted length and structures of the additional and facultative stem-loops represented in dark blue in the secondary structure diagram Analysis of operon structures has identified a large number of new candidate thiamin-regulated genes, mostly transporters, in various prokaryotic organisms. The x-ray crystal structure of the TPP riboswitch aptamer has been solved.

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

In enzymology, a hydroxyethylthiazole kinase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">5-Aminoimidazole ribotide</span> Chemical compound

5′-Phosphoribosyl-5-aminoimidazole is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, and hence is a building block for DNA and RNA. The vitamins thiamine and cobalamin also contain fragments derived from AIR. It is an intermediate in the adenine pathway and is synthesized from 5′-phosphoribosylformylglycinamidine by AIR synthetase.

<span class="mw-page-title-main">5′-Phosphoribosylformylglycinamidine</span> Chemical compound

5′-Phosphoribosylformylglycinamidine is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, and hence is a building block for DNA and RNA. The vitamins thiamine and cobalamin also contain fragments derived from FGAM.

<span class="mw-page-title-main">Glycineamide ribonucleotide</span> Chemical compound

Glycineamide ribonucleotide is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, and hence is a building block for DNA and RNA. The vitamins thiamine and cobalamin also contain fragments derived from GAR.

Sulfur carrier protein ThiS adenylyltransferase is an enzyme with systematic name ATP:(ThiS) adenylyltransferase. This enzyme catalyses the following chemical reaction

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

Thiazole synthase (EC 2.8.1.10, thiG (gene)) is an enzyme with systematic name 1-deoxy-D-xylulose 5-phosphate:thiol sulfurtransferase. This enzyme catalyses the following chemical reaction

Aminopyrimidine aminohydrolase (EC 3.5.99.2, thiaminase, thiaminase II, tenA (gene)) is an enzyme with systematic name 4-amino-5-aminomethyl-2-methylpyrimidine aminohydrolase. This enzyme catalyses the following chemical reaction

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

Phosphomethylpyrimidine synthase is an enzyme with systematic name 5-amino-1-(5-phospho-D-ribosyl)imidazole formate-lyase . This enzyme catalyses the following chemical reaction

References

  1. ↑ Jurgenson CT, Begley TP, Ealick SE (2009). "The structural and biochemical foundations of thiamin biosynthesis". Annual Review of Biochemistry. 78 (1): 569–603. doi:10.1146/annurev.biochem.78.072407.102340. PMC   6078420 . PMID   19348578.
  2. 1 2 Roje S (July 2007). "Vitamin B biosynthesis in plants". Phytochemistry. 68 (14): 1904–21. Bibcode:2007PChem..68.1904R. doi:10.1016/j.phytochem.2007.03.038. PMID   17512961.
  3. ↑ Broderick JB, Duffus BR, Duschene KS, Shepard EM (April 2014). "Radical S-adenosylmethionine enzymes". Chemical Reviews. 114 (8): 4229–317. doi:10.1021/cr4004709. PMC   4002137 . PMID   24476342.
  4. ↑ Chatterjee A, Li Y, Zhang Y, Grove TL, Lee M, Krebs C, Booker SJ, Begley TP, Ealick SE (December 2008). "Reconstitution of ThiC in thiamine pyrimidine biosynthesis expands the radical SAM superfamily". Nature Chemical Biology. 4 (12): 758–65. doi:10.1038/nchembio.121. PMC   2587053 . PMID   18953358.
  5. 1 2 Spenser ID, White RL (May 1997). "Biosynthesis of vitamin B1 (thiamin): an instance of biochemical diversity". Angewandte Chemie International Edition in English. 36 (10): 1032–46. doi:10.1002/anie.199710321.
  6. ↑ Begley TP, Chatterjee A, Hanes JW, Hazra A, Ealick SE (April 2008). "Cofactor biosynthesis--still yielding fascinating new biological chemistry". Current Opinion in Chemical Biology. 12 (2): 118–25. doi:10.1016/j.cbpa.2008.02.006. PMC   2677635 . PMID   18314013.
  7. ↑ Zeidler J, Sayer BG, Spenser ID (October 2003). "Biosynthesis of vitamin B1 in yeast. Derivation of the pyrimidine unit from pyridoxine and histidine. Intermediacy of urocanic acid". Journal of the American Chemical Society. 125 (43): 13094–105. doi:10.1021/ja030261j. PMID   14570482.
  8. ↑ Lai RY, Huang S, Fenwick MK, Hazra A, Zhang Y, Rajashankar K, et al. (June 2012). "Thiamin pyrimidine biosynthesis in Candida albicans : a remarkable reaction between histidine and pyridoxal phosphate". Journal of the American Chemical Society. 134 (22): 9157–9. doi:10.1021/ja302474a. PMC   3415583 . PMID   22568620.
  9. ↑ Lawhorn BG, Mehl RA, Begley TP (September 2004). "Biosynthesis of the thiamin pyrimidine: the reconstitution of a remarkable rearrangement reaction". Organic & Biomolecular Chemistry. 2 (17): 2538–46. doi:10.1039/B405429F. PMID   15326535.
  10. ↑ Himmeldirk K, Sayer BG, Spenser ID (April 1998). "Comparative biogenetic anatomy of vitamin B1: a 13C NMR investigation of the biosynthesis of thiamin in Escherichia coli and in Saccharomyces cerevisiae". Journal of the American Chemical Society. 120 (15): 3581–9. doi:10.1021/ja973835r.
  11. ↑ Bazurto JV, Downs DM (February 2011). "Plasticity in the purine-thiamine metabolic network of Salmonella". Genetics. 187 (2): 623–31. doi:10.1534/genetics.110.124362. PMC   3030501 . PMID   21135073.
  12. ↑ Bazurto JV, Heitman NJ, Downs DM (September 2015). Metcalf WW (ed.). "Aminoimidazole Carboxamide Ribotide Exerts Opposing Effects on Thiamine Synthesis in Salmonella enterica". Journal of Bacteriology. 197 (17): 2821–30. doi:10.1128/JB.00282-15. PMC   4524041 . PMID   26100042.
  13. ↑ Goyer A (October 2010). "Thiamine in plants: aspects of its metabolism and functions". Phytochemistry. 71 (14–15): 1615–24. Bibcode:2010PChem..71.1615G. doi:10.1016/j.phytochem.2010.06.022. PMID   20655074.
  14. ↑ Jurgenson CT, Ealick SE, Begley TP (August 2009). "Biosynthesis of Thiamin Pyrophosphate". EcoSal Plus. 3 (2). doi:10.1128/ecosalplus.3.6.3.7. PMC   6039189 . PMID   26443755.
  15. ↑ Settembre E, Begley TP, Ealick SE (December 2003). "Structural biology of enzymes of the thiamin biosynthesis pathway". Current Opinion in Structural Biology. 13 (6): 739–47. doi:10.1016/j.sbi.2003.10.006. PMID   14675553.
  16. ↑ Bocobza SE, Aharoni A (October 2008). "Switching the light on plant riboswitches". Trends in Plant Science. 13 (10): 526–33. doi:10.1016/j.tplants.2008.07.004. PMID   18778966.
  17. ↑ Eggersdorfer M, Laudert D, Létinois U, McClymont T, Medlock J, Netscher T, Bonrath W (December 2012). "One hundred years of vitamins-a success story of the natural sciences". Angewandte Chemie. 51 (52): 12960–90. doi:10.1002/anie.201205886. PMID   23208776.
  18. ↑ Burdick D (2000). "Thiamine (B1)". Kirk-Othmer Encyclopedia of Chemical Technology. American Cancer Society. doi:10.1002/0471238961.2008090102211804.a01. ISBN   9780471238966.
  19. ↑ Revuelta JL, Buey RM, Ledesma-Amaro R, Vandamme EJ (September 2016). "Microbial biotechnology for the synthesis of (pro)vitamins, biopigments and antioxidants: challenges and opportunities". Microbial Biotechnology. 9 (5): 564–7. doi:10.1111/1751-7915.12379. PMC   4993173 . PMID   27373767.
  20. ↑ Hanson AD, Amthor JS, Sun J, Niehaus TD, Gregory JF, Bruner SD, Ding Y (August 2018). "Redesigning thiamin synthesis: Prospects and potential payoffs". Plant Science. 273: 92–99. doi: 10.1016/j.plantsci.2018.01.019 . PMID   29907313. S2CID   49217720.
  21. ↑ Acevedo-Rocha CG, Gronenberg LS, Mack M, Commichau FM, Genee HJ (August 2018). "Microbial cell factories for the sustainable manufacturing of B vitamins". Current Opinion in Biotechnology. 56: 18–29. doi: 10.1016/j.copbio.2018.07.006 . PMID   30138794.
  22. ↑ WOapplication 2017103221,Gronenberg L, Ferla M, Genee M,"A Genetically Modified Bacterial Cell Factory for Thiamine Production",published 22 June 2017, assigned to Biosyntia APS
  23. ↑ USapplication 2009233296,Goese M, Perkins J, Schyns G,"Thiamin production by fermentation",published 17 September 2009, assigned to DSM IP Assets B.V.
  24. ↑ Goyer A (April 2017). "Thiamin biofortification of crops". Current Opinion in Biotechnology. 44: 1–7. doi: 10.1016/j.copbio.2016.09.005 . PMID   27750185.
  25. ↑ Dong W, Thomas N, Ronald PC, Goyer A (2016). "Overexpression of Thiamin Biosynthesis Genes in Rice Increases Leaf and Unpolished Grain Thiamin Content But Not Resistance to Xanthomonas oryzae pv. oryzae". Frontiers in Plant Science. 7: 616. doi: 10.3389/fpls.2016.00616 . PMC   4861732 . PMID   27242822.
  26. ↑ Ahn IP, Kim S, Lee YH (July 2005). "Vitamin B1 functions as an activator of plant disease resistance". Plant Physiology. 138 (3): 1505–15. doi:10.1104/pp.104.058693. PMC   1176421 . PMID   15980201.
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