4-Amino-5-hydroxymethyl-2-methylpyrimidine explained

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).

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.[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.[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.

Related technologies

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]

Notes and References

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

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