UniProtKB/Swiss-Prot P14920: Variant p.Arg199Trp

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 199 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: LB/B The variants are classified into three categories: LP/P, LB/B and US.

• LP/P: likely pathogenic or pathogenic.
• LB/B: likely benign or benign.
• US: uncertain significance

Residue change: From Arginine (R) to Tryptophan (W) at position 199 (R199W, p.Arg199Trp). Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.
Physico-chemical properties: Change from large size and basic (R) to large size and aromatic (W) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: -3 The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:

• Lowest score: -4 (low probability of substitution).
• Highest score: 11 (high probability of substitution).

More information can be found on the following page
Variant description: Found in a patient with ALS; decreased function in D-serine catabolic process; 3- to 4-fold decrease in Vmax with D-serine, D-alanine and D-proline as substrates; impairs FAD binding; decreased affinity for D-serine, D-alanine and D-proline; leads to tetramerization of the holoenzyme; leads to the formation of ubiquitinated protein aggregates; promotes induction of apoptosis; causes cell death in motor neurons in a manner at least partially dependent on the N-methyl-D-aspartic acid receptor. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs139166976 [ dbSNP | Ensembl ]

Sequence information

Variant position: 199 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: 347 The length of the canonical sequence.
Location on the sequence: VNCTGVWAGALQRDPLLQPG R GQIMKVDAPWMKHFILTHDP The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.
Sequence annotation in neighborhood: The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:

• Type: the type of sequence feature.
• Positions: endpoints of the sequence feature.
• Description: contains additional information about the feature.

Type	Positions	Description
Chain	1 – 347	D-amino-acid oxidase
Binding site	182 – 182
Mutagenesis	183 – 183	G -> R. Abolishes activity. Impairs the ability to bind the FAD cofactor. Impairs targeting to peroxisomes and results in abnormal peroxisomal morphology. Leads to the formation of ubiquitinated protein aggregates and the induction of apoptosis.
Mutagenesis	219 – 219	P -> L. Increases catalytic efficiency and inhibition by benzoate.
Beta strand	196 – 206

Literature citations

Structural and mechanistic insights into ALS patient derived mutations in D-amino acid oxidase.
Khan S.; Upadhyay S.; Dave U.; Kumar A.; Gomes J.;
Int. J. Biol. Macromol. 256:128403-128403(2024)
Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF VARIANT ALS HIS-38 IN COMPLEX WITH FAD AND INHIBITOR BENZOATE; FUNCTION; CATALYTIC ACTIVITY; COFACTOR; BIOPHYSICOCHEMICAL PROPERTIES; SUBUNIT; CHARACTERIZATION OF VARIANTS ALS HIS-38; TRP-199 AND ARG-201;
Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase.
Mitchell J.; Paul P.; Chen H.J.; Morris A.; Payling M.; Falchi M.; Habgood J.; Panoutsou S.; Winkler S.; Tisato V.; Hajitou A.; Smith B.; Vance C.; Shaw C.; Mazarakis N.D.; de Belleroche J.;
Proc. Natl. Acad. Sci. U.S.A. 107:7556-7561(2010)
Cited for: CHARACTERIZATION OF VARIANT ALS TRP-199; FUNCTION; CATALYTIC ACTIVITY; SUBUNIT; SUBCELLULAR LOCATION;
D-amino acid oxidase controls motoneuron degeneration through D-serine.
Sasabe J.; Miyoshi Y.; Suzuki M.; Mita M.; Konno R.; Matsuoka M.; Hamase K.; Aiso S.;
Proc. Natl. Acad. Sci. U.S.A. 109:627-632(2012)
Cited for: CHARACTERIZATION OF VARIANT ALS TRP-199; FUNCTION; CATALYTIC ACTIVITY;
Pathogenic effects of amyotrophic lateral sclerosis-linked mutation in D-amino acid oxidase are mediated by D-serine.
Paul P.; Murphy T.; Oseni Z.; Sivalokanathan S.; de Belleroche J.S.;
Neurobiol. Aging 35:876-885(2014)
Cited for: CHARACTERIZATION OF VARIANT ALS TRP-199; TISSUE SPECIFICITY; MUTAGENESIS OF GLY-183;
Structure-function relationships in human d-amino acid oxidase variants corresponding to known SNPs.
Cappelletti P.; Piubelli L.; Murtas G.; Caldinelli L.; Valentino M.; Molla G.; Pollegioni L.; Sacchi S.;
Biochim. Biophys. Acta 1854:1150-1159(2015)
Cited for: CHARACTERIZATION OF VARIANTS ALS TRP-199; GLN-199 AND ARG-209; FUNCTION; CATALYTIC ACTIVITY; COFACTOR; BIOPHYSICOCHEMICAL PROPERTIES;