Limits...
Axonal neuropathy with neuromyotonia: there is a HINT

View Article: PubMed Central - PubMed

ABSTRACT

Mutations in HINT1 cause a common, autosomal-recessive, axonal Charcot-Marie-Tooth neuropathy, often with neuromyotonia. Peeters et al. summarize neurological aspects of the disease, epidemiology and mutation spectrum, and structural and functional characteristics of the affected protein. They propose guidelines to recognize and differentiate HINT1-neuropathy and suggest strategies to treat common symptoms.

No MeSH data available.


HINT1 structure and known mutations. (A) Reaction scheme for cleavage of AMP-linked compounds by the HINT1 enzyme, adapted from Krakowiak et al. (2014). (B and C). Position of the 12 known HINT1 mutations on the cDNA and protein structures, respectively. (D) 3D representation of the HINT1 dimer, highlighting the eight amino acid residues targeted by missense mutations. HINT1 monomers are shown in blue and yellow.
© Copyright Policy - cc-by-nc
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5382946&req=5

aww301-F3: HINT1 structure and known mutations. (A) Reaction scheme for cleavage of AMP-linked compounds by the HINT1 enzyme, adapted from Krakowiak et al. (2014). (B and C). Position of the 12 known HINT1 mutations on the cDNA and protein structures, respectively. (D) 3D representation of the HINT1 dimer, highlighting the eight amino acid residues targeted by missense mutations. HINT1 monomers are shown in blue and yellow.

Mentions: The endogenous substrate(s) of HINT1 remain unknown; nevertheless, it appears to be a promiscuous enzyme in vitro (Gilmour et al., 1997; Bieganowski et al., 2002; Chou and Wagner, 2007; Ozga et al., 2010; Wang et al., 2012). The general formula of HINT1 substrates is NMP-X [X = -NHR, -OC(O)R, -S] (Krakowiak et al., 2014) (Fig. 3A). HINT1 preferentially hydrolyses adenosine derivatives with a single phosphate, including phosphoramidates (AMP-NH2, AMP-N-ɛ-lysine, AMP-alanine) and aminoacyl adenylates (see below) (Bieganowski et al., 2002; Wang et al., 2012). Known HINT1 inhibitors are sulfamoyl adenosine and N-ethylsulfamyol adenosine (Krakowiak et al., 2004). Crystallographic analysis of HINT1 in complex with artificial substrates has elucidated its catalytic mechanism of action as follows (Lima et al., 1997; Krakowiak et al., 2004; Wang et al., 2012): (i) recognition of the NMP-X substrate: the nucleotide part binds in the HIT nucleotide-binding cleft and, in case the side-chain is an alkylamide, its alkyl portion binds the C-terminal Trp123 residue located across the dimer interface; (ii) nucleophilic attack by the His112 residue on the α-phosphate of the substrate; (iii) formation of a covalent nucleotidyl phospho-HINT1 intermediate (adenylylation); and (iv) hydrolysis of the nucleotide and release of the catalytic products (Fig. 3A).Figure 3


Axonal neuropathy with neuromyotonia: there is a HINT
HINT1 structure and known mutations. (A) Reaction scheme for cleavage of AMP-linked compounds by the HINT1 enzyme, adapted from Krakowiak et al. (2014). (B and C). Position of the 12 known HINT1 mutations on the cDNA and protein structures, respectively. (D) 3D representation of the HINT1 dimer, highlighting the eight amino acid residues targeted by missense mutations. HINT1 monomers are shown in blue and yellow.
© Copyright Policy - cc-by-nc
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382946&req=5

aww301-F3: HINT1 structure and known mutations. (A) Reaction scheme for cleavage of AMP-linked compounds by the HINT1 enzyme, adapted from Krakowiak et al. (2014). (B and C). Position of the 12 known HINT1 mutations on the cDNA and protein structures, respectively. (D) 3D representation of the HINT1 dimer, highlighting the eight amino acid residues targeted by missense mutations. HINT1 monomers are shown in blue and yellow.
Mentions: The endogenous substrate(s) of HINT1 remain unknown; nevertheless, it appears to be a promiscuous enzyme in vitro (Gilmour et al., 1997; Bieganowski et al., 2002; Chou and Wagner, 2007; Ozga et al., 2010; Wang et al., 2012). The general formula of HINT1 substrates is NMP-X [X = -NHR, -OC(O)R, -S] (Krakowiak et al., 2014) (Fig. 3A). HINT1 preferentially hydrolyses adenosine derivatives with a single phosphate, including phosphoramidates (AMP-NH2, AMP-N-ɛ-lysine, AMP-alanine) and aminoacyl adenylates (see below) (Bieganowski et al., 2002; Wang et al., 2012). Known HINT1 inhibitors are sulfamoyl adenosine and N-ethylsulfamyol adenosine (Krakowiak et al., 2004). Crystallographic analysis of HINT1 in complex with artificial substrates has elucidated its catalytic mechanism of action as follows (Lima et al., 1997; Krakowiak et al., 2004; Wang et al., 2012): (i) recognition of the NMP-X substrate: the nucleotide part binds in the HIT nucleotide-binding cleft and, in case the side-chain is an alkylamide, its alkyl portion binds the C-terminal Trp123 residue located across the dimer interface; (ii) nucleophilic attack by the His112 residue on the α-phosphate of the substrate; (iii) formation of a covalent nucleotidyl phospho-HINT1 intermediate (adenylylation); and (iv) hydrolysis of the nucleotide and release of the catalytic products (Fig. 3A).Figure 3

View Article: PubMed Central - PubMed

ABSTRACT

Mutations in HINT1 cause a common, autosomal-recessive, axonal Charcot-Marie-Tooth neuropathy, often with neuromyotonia. Peeters et al. summarize neurological aspects of the disease, epidemiology and mutation spectrum, and structural and functional characteristics of the affected protein. They propose guidelines to recognize and differentiate HINT1-neuropathy and suggest strategies to treat common symptoms.

No MeSH data available.