Glucopyranosyloxymethyluracil

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Structural formula
D-glucopyranosyloxymethyluracil, shown is the naturally occurring β-anomer
General
Surname Glucopyranosyloxymethyluracil
other names
  • Base J
  • 5-glucopyranosyloxymethyl-2,4 (1 H , 3 H ) -pyrimidinedione
Molecular formula C 11 H 18 N 2 O 8
External identifiers / databases
CAS number 53910-89-7
Wikidata Q1532320
properties
Molar mass 306.27 g mol −1
Physical state

firmly

safety instructions
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

D -Glucopyranosyloxymethyluracil is a nucleobase and is derived from uracil . The abbreviation for this base is “ J ” (Base J). It was identified in 1993 as a component of nuclear deoxyribonucleic acid (DNA) in Trypanosoma brucei , the causative agent of African sleeping sickness , and is the first hypermodified nucleic acid base of eukaryotic DNA to be discovered.

Occurrence

D- glucopyranosyloxymethyluracil was discovered in all of the kinetoplastids investigated to date , for example in leishmanias ( Leishmania donovani ) or trypanosomes (e.g. Trypanosoma brucei , Trypanosoma cruzi , Trypanosoma borelli ). These are mostly parasitic causes of various diseases.

The base is also found in the marine flagellate Diplonema and in Euglena gracilis , a unicellular alga . In contrast, the base could be found in other protozoa , fungi or vertebrates , e.g. B. in humans, cannot be detected.

Distribution within the DNA

β- D -glucopyranosyloxymethyluracil often occurs as base J in repetitive DNA sequences of described organisms, often in the teleomeric segments. On average, approximately 1% of the thymine present is replaced by J. The distribution of J in teleomeric sections fluctuates depending on the organism. In T. brucei , J occurs 50% therein, while in Euglena most of the J does not occur there. In Crithidia fasciculata, on the other hand, the majority, about 98%, is located in the telomeres.

A peculiarity can be observed in T. brucei . During the phase in which the parasite lives in the intermediate host, the tsetse fly , the base J was not detected. Other trypanosomes, such as T. cruzi or L. donovani , contain D- glucopyranosyloxymethyluracil in both life cycles.

structure

D -Glucopyranosyloxymethyluracil is a glucoside . Here, D - glucose is glycosidically linked to hydroxymethyluracil via its 1'-OH group . In the DNA of organisms described, the β- anomer of glucose was always described.

biosynthesis

In the organism, D- glucopyranosyloxymethyluracil is synthesized in a two-step reaction from deoxythymidine in DNA (dT) (see picture). A thymidine hydroxylase (TH, A in the figure) recognizes deoxythymidine ( 1 ) and oxidizes the methyl group so that hydroxymethyldeoxyuridine (HOCH 2 -dU, 2 ) is formed. This is then converted to β- D- glucosyl-5- (hydroxymethyl) uracil ( 3 ) with consumption of one molecule of D - glucose , which catalyzes a glucosyl transferase ( B ).

Synthesis of D-glucopyranosyloxymethyluracil

Technical representation

The base can also be represented in organic chemistry, for example starting from 5-hydroxymethyl-2-deoxyuridine (HOCH 3 -dU) or thymdine.

J-binding proteins

JBP1

In mammals, methylated cytosine (MeC) is recognized by MeC binding proteins, which changes the chromatin structure . Similarly, a J-binding protein (JBP1) was identified that recognizes the base J and interacts with it. This makes it one of the DNA binding proteins. In C. fasciculata this is 90 kDa, and homologous proteins have also been discovered in other organisms.

In many kinetoplastids the amount of JBP1 is very low, which indicates that this protein has a catalytic function. For the function of JBP1 it has been suggested that it plays a role in the biosynthesis of J. It should bind to J and thereby direct the glucosyltransferase to neighboring thymine bases that have already been modified by the thymidine hydroxylase. This maintains the number of J in the immediate vicinity.

This JBP1-mediated maintenance of the amount of J in DNA is supported by an observation in T. brucei . If the gene for JBP1 is inactivated there, the content of J in the DNA drops to 5% compared to the wild type. In Leishmania tarentolae and Leishmania major , switching off the gene is even fatal.

JBP2

JBP2 was identified in T. brucei and a 120 kDa homologue to JBP1 was discovered. Its N-terminus is 34% identical to that of JBP1 and 47% similar. The C-terminus also shows similar matches with that of JBP1 (24% identical, 45% similar). The parasite is only expressed when it is in a mammal's bloodstream . In contrast to JBP1, however, it does not interact with the DNA, so that, strictly speaking, the name is wrong.

JBP2 was also discovered in other organisms mentioned above. It is discussed whether JBP2 is important for the de novo and site-specific synthesis of J. JBP1 and JBP2 could also work together here: If T. brucei does not express any of these proteins, the base can no longer be formed there.

Biological significance of the base

The exact meaning of the base is not yet known. Initially it was assumed that the base plays a role in gene silencing - analogous to how MeC can repress genes in vertebrates and plants . However, recent studies speak against it.

Possibly the base influences the homologous recombination between repetitive sequences, which has also been suggested for MeC from other eukaryotes. Whether the base plays a role in relation to the telomeres is controversial. This would be supported by the fact that in C. fasciculata or some leishmanias the largest part of the base can be found there. In other species, however, such a possible function does not necessarily have to be exercised, for example in Euglena . There is only a fraction of J in the telomeres.

Since most kinetoplastids, but not their hosts , contain this base, disruption of biosynthesis is a target for parasite-specific treatment. However, this assumes that the biological significance of the base is recognized and understood first.

literature

Individual evidence

  1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  2. ↑ Gommers-Ampt, JH. and Borst, P. (1995): Hypermodified bases in DNA , in: FASEB J , 9  (11); Pp. 1034-1042 ( PMID 7649402 ; PDF ).
  3. ↑ Martin de Kort, Edwin Ebrahimi, Eric R. Wijsman, Gijs A. van der Marel, Jacques H. van Boom (1999): Synthesis of Oligodeoxynucleotides Containing 5 - (- D-Glucopyranosyloxymethyl) -2-deoxyuridine, a Modified Nucleoside in the DNA of Trypanosoma brucei , in: European Journal of Organic Chemistry , 1999 (9), pp. 2337-2344 ( doi : 10.1002 / (SICI) 1099-0690 (199909) 1999: 9 <2337 :: AID-EJOC2337> 3.0 .CO; 2-F ).