Base J

• Base J
• 5 Glucopyranosyloxymethyl -2, 4 (1H, 3H) -pyrimidinedione

Fixed

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D- Glucopyranosyloxymethyluracil is a nucleic base and derived from uracil. The shorthand notation for this base is " J" (base J). It was in 1993 as part of nuclear deoxyribonucleic acid ( DNA) in Trypanosoma brucei, the causative agent of African sleeping sickness identified, and is the first discovered hyper -modified nucleobase eukaryotic DNA.

Occurrence

D- Glucopyranosyloxymethyluracil was detected in all investigated so far kinetoplastids, such as Leishmania ( Leishmania donovani ) or trypanosomes (eg, Trypanosoma brucei, Trypanosoma cruzi, Trypanosoma borelli ). These are mostly parasitic cause of various diseases.

The base is also present in the marine flagellate Diplonema and in Euglena gracilis, a unicellular alga. By contrast, could the base in other protozoa, fungi, or vertebrates, for example, in people, not be detected.

Dissemination within the DNA

β -D occurs as the base Glucopyranosyloxymethyluracil J frequently repetitive DNA sequences described organisms, often in teleomeren sections. On average, the occurring thymine are replaced by J in approximately 1%. The distribution of J in teleomeren sections fluctuates depending on the organism. In T. brucei J comes to 50 % before it, while in Euglena most J does not occur there. In Crithidia fasciculata, however, is the majority, about 98 % localized to the telomeres.

A special feature is observed in T. brucei. During the phase in which the parasite in the intermediate host, the tsetse fly lives, that base J was not detected. Other trypanosomes, such as T. cruzi or L. donovani contain D- Glucopyranosyloxymethyluracil contrast, in both life cycles.

Structure

D- Glucopyranosyloxymethyluracil is a glucoside. Here, D-glucose is linked through its glycosidic 1' -OH group with hydroxymethyluracil. In the DNA described organisms always the β -anomer of the glucose has been described.

Biosynthesis

In the organism, D- glucopyranosyloxymethyluracil is in a two-step reaction of deoxythymidine into DNA (dT ) were synthesized (see picture). This recognizes a Thymidinhydroxylase (TH, A in the figure ) deoxythymidine (1) and oxidizes the methyl group, so that it creates Hydroxymethyldesoxyuridin ( HOCH3 -dU, 2). This is then converted to β - D-glucosyl -5-( hydroxymethyl ) uracil (3) with the consumption of one molecule of D-glucose, which is a glycosyltransferase catalyzed (B).

Technical presentation

J- binding proteins

JBP1

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

In many, the amount of Kinetoplastidae JBP1 is very low, indicating a catalytic function of this protein. For the function of JBP1 was proposed here is that it plays a role in the biosynthesis of J. This is supposed to bind to J and thereby direct the glucosyltransferase to adjacent, already modified by the Thymidinhydroxylase thymine bases. This reduces the number of J is maintained in the immediate vicinity.

These mediated by JBP1 maintaining the amount of J in DNA is supported by an observation in T. brucei. If there is, the gene is inactivated for JBP1, the content of Y decreases in DNA 5 % compared to the wild type. In Leishmania tarentolae, and Leishmania major turning off the gene is fatal.

JBP2

In T. brucei JBP2 was identified, a 120 -kDa homologue discovered to JBP1. Its N-terminus is identical and 47% similar to the JBP1 to 34%. Also, the C -terminus has analog matches with that of JBP1 to (24 % identical, 45 % similar ). Only when the parasite resides in the bloodstream of a mammal, it is expressed. However, in contrast to JBP1 it does not interact with the DNA, so that strictly speaking the name is incorrect.

In other abovementioned organisms JBP2 was discovered. It is discussed whether JBP2 is important for the de novo and site-specific synthesis of J. This could also JBP1 and JBP2 work together: If T. brucei expressed none of these proteins, the base can not be formed there.

Biological significance of the base

The exact meaning of the base is not yet known. At first conjectured that the base in gene silencing plays a role - similar to how MeC can repress in vertebrates and plant genes. Recent studies speak against it.

Maybe the base affects the homologous recombination between repetitive sequences, which has also been proposed for MeC other eukaryotes. Whether the base exerts a role in relation to the telomeres, is controversial. But talks that in C. fasciculata or Leishmania is there some find most of the base. In other species such a possible function must, however, are not necessarily exercised, for example in Euglena. Where only a fraction of J is present in the telomers.

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