FPG IleRS zinc finger

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zf-FPG_IleRS
PDB 1tdz EBI.jpg
Crystal structure complex between the lactococcus lactis fpg (mutm) and a fapy-dg containing DNA
Identifiers
Symbolzf-FPG_IleRS
Pfam PF06827
Pfam clan CL0167
InterPro IPR010663
SCOP2 1qu2 / SCOPe / SUPFAM

The FPG IleRS zinc finger domain represents a zinc finger domain found at the C-terminal in both DNA glycosylase/AP lyase enzymes and in isoleucyl tRNA synthetase. In these two types of enzymes, the C-terminal domain forms a zinc finger.

DNA glycosylase/AP lyase enzymes are involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. These enzymes have both DNA glycosylase activity (EC) and AP lyase activity (EC). [1] Examples include formamidopyrimidine-DNA glycosylases (Fpg; MutM) and endonuclease VIII (Nei). Formamidopyrimidine-DNA glycosylases (Fpg, MutM) is a trifunctional DNA base excision repair enzyme that removes a wide range of oxidation-damaged bases (N-glycosylase activity; EC) and cleaves both the 3'- and 5'-phosphodiester bonds of the resulting apurinic/apyrimidinic site (AP lyase activity; EC). Fpg has a preference for oxidised purines, excising oxidized purine bases such as 7,8-dihydro-8-oxoguanine (8-oxoG). ITs AP (apurinic/apyrimidinic) lyase activity introduces nicks in the DNA strand, cleaving the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Fpg is a monomer composed of 2 domains connected by a flexible hinge. [2] The two DNA-binding motifs (a zinc finger and the helix-two-turns-helix motifs) suggest that the oxidized base is flipped out from double-stranded DNA in the binding mode and excised by a catalytic mechanism similar to that of bifunctional base excision repair enzymes. [2] Fpg binds one ion of zinc at the C terminus, which contains four conserved and essential cysteines. [3] Endonuclease VIII (Nei) has the same enzyme activities as Fpg above, but with a preference for oxidized pyrimidines, such as thymine glycol, 5,6-dihydrouracil and 5,6-dihydrothymine. [4] [5]

An Fpg-type zinc finger is also found at the C terminus of isoleucyl tRNA synthetase (EC). [6] [7] This enzyme catalyses the attachment of isoleucine to tRNA(Ile). As IleRS can inadvertently accommodate and process structurally similar amino acids such as valine, to avoid such errors it has two additional distinct tRNA(Ile)-dependent editing activities. One activity is designated as 'pre-transfer' editing and involves the hydrolysis of activated Val-AMP. The other activity is designated 'post-transfer' editing and involves deacylation of mischarged Val-tRNA(Ile). [8]

Related Research Articles

Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases.

Nuclease

A nuclease is an enzyme capable of cleaving the phosphodiester bonds between nucleotides of nucleic acids. Nucleases variously effect single and double stranded breaks in their target molecules. In living organisms, they are essential machinery for many aspects of DNA repair. Defects in certain nucleases can cause genetic instability or immunodeficiency. Nucleases are also extensively used in molecular cloning.

DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.

AP site Biochemical site of damaged DNA or RNA

In biochemistry and molecular genetics, an AP site, also known as an abasic site, is a location in DNA that has neither a purine nor a pyrimidine base, either spontaneously or due to DNA damage. It has been estimated that under physiological conditions 10,000 apurinic sites and 500 apyrimidinic may be generated in a cell daily.

Base excision repair DNA repair process

Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.

AP endonuclease Enzyme involved in DNA repair

Apurinic/apyrimidinic (AP) endonuclease is an enzyme that is involved in the DNA base excision repair pathway (BER). Its main role in the repair of damaged or mismatched nucleotides in DNA is to create a nick in the phosphodiester backbone of the AP site created when DNA glycosylase removes the damaged base.

MUTYH

MUTYH is a human gene that encodes a DNA glycosylase, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the base excision repair pathway. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage.

Nucleotidyltransferase

Nucleotidyltransferases are transferase enzymes of phosphorus-containing groups, e.g., substituents of nucleotidylic acids or simply nucleoside monophosphates. The general reaction of transferring a nucleoside monophosphate moiety from A to B, can be written as:

Nuclease S1

Nuclease S1 is an endonuclease enzyme that splits single-stranded DNA (ssDNA) and RNA into oligo- or mononucleotides. This enzyme catalyses the following chemical reaction

APEX1

DNA-(apurinic or apyrimidinic site) lyase is an enzyme that in humans is encoded by the APEX1 gene.

In enzymology, an isoleucine-tRNA ligase is an enzyme that catalyzes the chemical reaction

In enzymology, DNA-(apurinic or apyrimidinic site) lyase, also referred to as DNA-(apurinic or apyrimidinic site) 5'-phosphomonoester-lyase or DNA AP lyase is a class of enzyme that catalyzes the chemical reaction of the cleavage of the C3'-O-P bond 3' from the apurinic or apyrimidinic site in DNA via beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate. In the 1970s, this class of enzyme was found to repair at apurinic or apyrimidinic DNA sites in E. coli and in mammalian cells. The major active enzymes of this class in bacteria, and specifically, E. coli is endonuclease type III. This enzyme encompasses a family of lyases that cleave carbon-oxygen bonds.

NTHL1

Endonuclease III-like protein 1 is an enzyme that in humans is encoded by the NTHL1 gene.

NEIL1

Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the NEIL1 gene.

NEIL2

Endonuclease VIII-like 2 is an enzyme that in humans is encoded by the NEIL2 gene.

DNA demethylation Removal of a methyl group from one or more nucleotides within an DNA molecule.

In mammals, DNA demethylation causes replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C). DNA demethylation can occur by an active process at the site of a 5mC in a DNA sequence or, in replicating cells, by preventing addition of methyl groups to DNA so that the replicated DNA will largely have cytosine in the DNA sequence.

H2TH domain

In molecular biology, the H2TH domain is a DNA-binding domain found in DNA glycosylase/AP lyase enzymes, which are involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Most damage to bases in DNA is repaired by the base excision repair pathway. These enzymes are primarily from bacteria, and have both DNA glycosylase activity EC 3.2.2.- and AP lyase activity EC 4.2.99.18. Examples include formamidopyrimidine-DNA glycosylases and endonuclease VIII (Nei).

NEIL3

Nei endonuclease VIII-like 3 is a protein in humans that is encoded by the NEIL3 gene.

DNA-formamidopyrimidine glycosylase is an enzyme with systematic name DNA glycohydrolase . FPG is a base excision repair enzyme which recognizes and removes a wide range of oxidized purines from correspondingly damaged DNA. It was discovered by Zimbabwean scientist Christopher J. Chetsanga in 1975.

Double-stranded uracil-DNA glycosylase is an enzyme with systematic name uracil-double-stranded DNA deoxyribohydrolase (uracil-releasing). This enzyme catalyses a specific chemical reaction: it hydrolyses mismatched double-stranded DNA and polynucleotides, releasing free uracil.

References

  1. ↑ Gilboa R, Zharkov DO, Golan G, Fernandes AS, Gerchman SE, Matz E, Kycia JH, Grollman AP, Shoham G (May 2002). "Structure of formamidopyrimidine-DNA glycosylase covalently complexed to DNA". J. Biol. Chem. 277 (22): 19811–6. doi: 10.1074/jbc.M202058200 . PMID   11912217.
  2. 1 2 Sugahara M, Mikawa T, Kumasaka T, Yamamoto M, Kato R, Fukuyama K, Inoue Y, Kuramitsu S (August 2000). "Crystal structure of a repair enzyme of oxidatively damaged DNA, MutM (Fpg), from an extreme thermophile, Thermus thermophilus HB8". EMBO J. 19 (15): 3857–69. doi:10.1093/emboj/19.15.3857. PMC   306600 . PMID   10921868.
  3. ↑ O'Connor TR, Graves RJ, de Murcia G, Castaing B, Laval J (April 1993). "Fpg protein of Escherichia coli is a zinc finger protein whose cysteine residues have a structural and/or functional role". J. Biol. Chem. 268 (12): 9063–70. PMID   8473347.
  4. ↑ Zharkov DO, Golan G, Gilboa R, Fernandes AS, Gerchman SE, Kycia JH, Rieger RA, Grollman AP, Shoham G (February 2002). "Structural analysis of an Escherichia coli endonuclease VIII covalent reaction intermediate". EMBO J. 21 (4): 789–800. doi:10.1093/emboj/21.4.789. PMC   125349 . PMID   11847126.
  5. ↑ Doublié S, Bandaru V, Bond JP, Wallace SS (July 2004). "The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity". Proc. Natl. Acad. Sci. U.S.A. 101 (28): 10284–9. doi:10.1073/pnas.0402051101. PMC   478564 . PMID   15232006.
  6. ↑ Silvian LF, Wang J, Steitz TA (August 1999). "Insights into editing from an ile-tRNA synthetase structure with tRNAile and mupirocin". Science. 285 (5430): 1074–7. doi:10.1126/science.285.5430.1074. PMID   10446055.
  7. ↑ Zhou L, Rosevear PR (November 1995). "Mutation of the carboxy terminal zinc finger of E. coli isoleucyl-tRNA synthetase alters zinc binding and aminoacylation activity". Biochem. Biophys. Res. Commun. 216 (2): 648–54. doi:10.1006/bbrc.1995.2671. PMID   7488160.
  8. ↑ Fukunaga R, Yokoyama S (June 2006). "Structural basis for substrate recognition by the editing domain of isoleucyl-tRNA synthetase". J. Mol. Biol. 359 (4): 901–12. doi:10.1016/j.jmb.2006.04.025. PMID   16697013.
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