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WO2000014221A1 - Transporteur de glycine - Google Patents

Transporteur de glycine Download PDF

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Publication number
WO2000014221A1
WO2000014221A1 PCT/GB1999/002909 GB9902909W WO0014221A1 WO 2000014221 A1 WO2000014221 A1 WO 2000014221A1 GB 9902909 W GB9902909 W GB 9902909W WO 0014221 A1 WO0014221 A1 WO 0014221A1
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WO
WIPO (PCT)
Prior art keywords
polypeptide
seq
sequence
polynucleotide
isolated
Prior art date
Application number
PCT/GB1999/002909
Other languages
English (en)
Inventor
David Malcolm Duckworth
Joanne Rachel Evans
Original Assignee
Smithkline Beecham P.L.C.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to EP99943113A priority Critical patent/EP1108020A1/fr
Priority to JP2000568965A priority patent/JP2003513609A/ja
Publication of WO2000014221A1 publication Critical patent/WO2000014221A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • the present invention relates to GLYTLIKE polynucleotides.
  • Such polynucleotides include:
  • (b) has an amino acid sequence which is at least 95%> identity, preferably at least 97-99% identity, to the amino acid sequence of SEQ ID NO:4 over the entire length of SEQ ID NO:4; (c) comprises the amino acid of SEQ ID NO:4; and
  • an isolated cDNA sequence will be incomplete, in that the region coding for the polypeptide does not extend all the way through to the 5' terminus. This is a consequence of reverse transcriptase, an enzyme with inherently low "processivity" (a measure of the ability of the enzyme to remain attached to the template during the polymerisation reaction), failing to complete a DNA copy of the mRNA template during first strand cDNA synthesis.
  • Nucleic acids for diagnosis may be obtained from a subject's cells, such as from blood, urine, saliva, tissue biopsy or autopsy material.
  • the genomic DNA may be used directly for detection or it may be amplified enzymatically by using PCR, preferably RT-PCR, or other amplification techniques prior to analysis.
  • RNA or cDNA may also be used in similar fashion. Deletions and insertions can be detected by a change in size of the amplified product in comparison to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to labeledGLYTLIKE nucleotide sequences. Perfectly matched sequences can be distinguished from mismatched duplexes by RNase digestion or by differences in melting temperatures.
  • DNA sequence difference may also be detected by alterations in the electrophoretic mobility of DNA fragments in gels, with or without denaturing agents, or by direct DNA sequencing (see, for instance, Myers et al., Science ( 1985) 230: 1242). Sequence changes at specific locations may also be revealed by nuclease protection assays, such as RNase and SI protection or the chemical cleavage method (see Cottoner al., Proc Natl Acad Sci USA (1985) 85: 4397-4401).
  • An array of oligonucleotides probes comprising GLYTLIKE polynucleotide sequence or fragments thereof can be constructed to conduct efficient screening of e.g., genetic mutations. Such arrays are preferably high density arrays or grids.
  • mapping of relevant sequences to chromosomes is an important first step in correlating those sequences with gene associated disease. Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found in, for example, V. McKusick, Mendelian Inheritance in Man (available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and diseases that have been mapped to the same chromosomal region are then identified through linkage analysis (co-inheritance of physically adjacent genes).
  • a further aspect of the present invention relates to antibodies.
  • the polypeptides of the invention or their fragments, or cells expressing them, can be used as immunogens to produce antibodies that are immunospecific for polypeptides of the present invention.
  • immunospecific means that the antibodies have substantially greater affinity for the polypeptides of the invention than their affinity for other related polypeptides in the prior art.
  • Polypeptides of the present invention have one or more biological functions that are of relevance in one or more disease states, in particular the diseases of the invention hereinbefore mentioned. It is therefore useful to to identify compounds that stimulate or inhibit the function or level of the polypeptide.
  • the present invention provides for a method of screening compounds to identify those that stimulate or inhibit the function or level of the polypeptide.
  • Such methods identify agonists or antagonists that may be employed for therapeutic and prophylactic purposes for such diseases of the invention as hereinbefore mentioned.
  • Compounds may be identified from a variety of sources, for example, cells, cell-free preparations, chemical libraries, collections of chemical compounds, and natural product mixtures.
  • Such agonists or antagonists so-identified may be natural or modified substrates, ligands, receptors, enzymes, etc., as the case may be, of the polypeptide; a structural or functional mimetic thereof (see Coligan etal, Current Protocols in Immunology l(2):Chapter 5 (1991)) or a small molecule.
  • Such small molecules preferably have a molecular weight below 2.000 daltons, more preferably between 300 and 1.000 daltons, and most preferably between 400 and 700 daltons. It is preferred that these small molecules are organic molecules.
  • a polypeptide of the present invention may be used to identify membrane bound or soluble receptors, if any, through standard receptor binding techniques known in the art. These include, but are not limited to, ligand binding and crosslinking assays in which the polypeptide islabeled with a radioactive isotope (for instance. ' - ⁇ 1). chemically modified (for instance, biotinylated). or fused to a peptide sequence suitable for detection or purification, and incubated with a source of the putative receptor (cells, cell membranes, cell supernatants. tissue extracts, bodily fluids). Other methods include biophysical techniques such as surface plasmon resonance and spectroscopy.
  • ligand binding and crosslinking assays in which the polypeptide islabeled with a radioactive isotope (for instance. ' - ⁇ 1). chemically modified (for instance, biotinylated). or fused to a peptide sequence suitable for detection or purification, and incubated with a source of the put
  • agonists and antagonists of polypeptides may also be used to identify agonists and antagonists of the polypeptide that compete with the binding of the polypeptide to its receptors, if any.
  • Standard methods for conducting such assays are well understood in the art.
  • antagonists of polypeptides of the present invention include antibodies or. in some cases, oligonucleotides or proteins that are closely related to the ligands, substrates, receptors, enzymes, etc., as the case may be, of the polypeptide, e.g., a fragment of the ligands, substrates, receptors, enzymes, etc.; or a small molecule that bind to the polypeptide of the present invention but do not elicit a response, so that the activity of the polypeptide is prevented.
  • polypeptide of the present invention (c) a cell membrane expressing a polypeptide of the present invention; or (d) an antibody to a polypeptide of the present invention; which polypeptide is preferably that of SEQ ID NO:2.
  • Antibodies as used herein includes polyclonal and monoclonal antibodies, chimeric, single chain, and humanized antibodies, as well as Fab fragments, including the products of an Fab or other immunoglobulin expression library.
  • Polynucleotide generally refers to any polyribonucleotide (RNA) or polydeoxribonucleotide (DNA). which may be unmodified or modified RNA or DNA. “Polynucleotides” include, without
  • Polypeptide refers to any polypeptide comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres.
  • Polypeptide refers to both short chains, commonly referred to as peptides, oligopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids.
  • Polypeptides include amino acid sequences modified either by natural processes, such as post- translational processing, or by chemical modification techniques that are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.
  • Modifications may occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present to the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched and branched cyclic polypeptides may result from post-translation natural processes or may be made by synthetic methods.
  • Modifications include acetylation, acylation, ADP-ribosylation, amidation, biotinylation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cystine, formation of pyroglutamate, formylation, gamma- carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization.
  • Variant refers to a polynucleotide or polypeptide that differs from a reference polynucleotide or polypeptide, but retains the essential properties thereof.
  • a typical variant of a polynucleotide differs in nucleotide sequence from the reference polynucleotide. Changes in the nucleotide sequence of the variant may or may not alter the amino acid sequence of a polypeptide encoded by the reference polynucleotide. Nucleotide changes may result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence, as discussed below.
  • a typical variant of a polypeptide differs in amino acid sequence from the reference polypeptide.
  • a variant and reference polypeptide may differ in amino acid sequence by one or more substitutions, insertions, deletions in any combination.
  • a substituted or inserted amino acid residue may or may not be one encoded by the genetic code. Typical conservative substitutions include Gly, Ala; Val, He, Leu; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe and Tyr.
  • a variant of a polynucleotide or polypeptide may be naturally occurring such as an allele, or it may be a variant that is not known to occur naturally.
  • Non-naturally occurring variants of polynucleotides and polypeptides may be made by mutagenesis techniques or by direct synthesis. Also included as variants are polypeptides having one or more post-translational modifications, for instance glycosylation. phosphorylation, methvlation, ADP ribosylation and the like. Embodiments include methvlation of the N-terminal amino acid, phosphorylations of serines and threonines and modification of C-terminal glycines.
  • Allele refers to one of two or more alternative forms of a gene occuring at a given locus in the genome.
  • Polymorphism refers to a variation in nucleotide sequence (and encoded polypeptide sequence. if relevant) at a given position in the genome within a population.
  • SNP Single Nucleotide Polymorphism
  • SNPs refers to the occurence of nucleotide variability at a single nucleotide position in the genome, within a population.
  • An SNP may occur within a gene or within intergenic regions of the genome.
  • SNPs can be assayed using Allele Specific Amplification (ASA).
  • ASA Allele Specific Amplification
  • a common primer is used in reverse complement to the polymorphism being assayed. This common primer can be between 50 and 1500 bps from the polymorphic base.
  • the other two (or more) primers are identical to each other except that the final 3' base wobbles to match one of the two (or more) alleles that make up the polymorphism.
  • RNA molecules produced from RNA molecules initially transcribed from the same genomic DNA sequence but which have undergone alternative RNA splicing.
  • Alternative RNA splicing occurs when a primary RNA transcript undergoes splicing, generally for the removal of introns, which results in the production of more than one mRNA molecule each of that may encode different amino acid sequences.
  • the term splice variant also refers to the proteins encoded by the above cDNA molecules.
  • Identity reflects a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, determined by comparing the sequences. In general, identity refers to an exact nucleotide to nucleotide or amino acid to amino acid correspondence of the two polynucleotide or two polypeptide sequences, respectively, over the length of the sequences being compared. "% Identity” - For sequences where there is not an exact correspondence, a “% identity” may be determined. In general, the two sequences to be compared are aligned to give a maximum correlation between the sequences. This may include inserting "gaps" in either one or both sequences, to enhance the degree of alignment.
  • a % identity may be determined over the whole length of each of the sequences being compared (so-called global alignment), that is particularly suitable for sequences of the same or very similar length, or over shorter, defined lengths (so-called local alignment), that is more suitable for sequences of unequal length.
  • Similarity is a further, more sophisticated measure of the relationship between two polypeptide sequences.
  • similarity means a comparison between the amino acids of two polypeptide chains, on a residue by residue basis, taking into account not only exact correspondences between a between pairs of residues, one from each of the sequences being compared (as for identity) but also, where there is not an exact correspondence, whether, on an evolutionary basis, one residue is a likely substitute for the other. This likelihood has an associated “score” from which the "% similarity" of the two sequences can then be determined. Methods for comparing the identity and similarity of two or more sequences are well known in the art.
  • programs available in the Wisconsin Sequence Analysis Package, version 9.1 may be used to determine the % identity between two polynucleotides and the %> identity and the % similarity between two polypeptide sequences.
  • BESTFIT uses the "local homology” algorithm of Smith and Waterman (J Mol Biol, 147, 195- 197, 1981, Advances in Applied Mathematics, 2, 482-489, 1981) and finds the best single region of similarity between two sequences.
  • BESTFIT is more suited to comparing two polynucleotide or two polypeptide sequences that are dissimilar in length, the program assuming that the shorter sequence represents a portion of the longer.
  • GAP aligns two sequences, finding a "maximum similarity", according to the algorithm of Neddleman and Wunsch (J Mol Biol, 48, 443-453, 1970).
  • GAP is more suited to comparing sequences that are approximately the same length and an alignment is expected over the entire length.
  • the parameters "Gap Weight” and "Length Weight” used in each program are 50 and 3, for polynucleotide sequences and 12 and 4 for polypeptide sequences, respectively.
  • % identities and similarities are determined when the two sequences being compared are optimally aligned.
  • the BLOSUM62 amino acid substitution matrix (Henikoff S and Henikoff J G, Proc. Nat. Acad Sci. USA, 89, 10915- 10919, 1992) is used in polypeptide sequence comparisons including where nucleotide sequences are first translated into amino acid sequences before comparison.
  • the program BESTFIT is used to determine the % identity of a query polynucleotide or a polypeptide sequence with respect to a reference polynucleotide or a polypeptide sequence, the query and the reference sequence being optimally aligned and the parameters of the program set at the default value, as hereinbefore described.
  • Identity Index is a measure of sequence relatedness which may be used to compare a candidate sequence (polynucleotide or polypeptide) and a reference sequence.
  • a candidate polynucleotide sequence having, for example, an Identity Index of 0.95 compared to a reference polynucleotide sequence is identical to the reference sequence except that the candidate polynucleotide sequence may include on average up to five differences per each 100 nucleotides of the reference sequence. Such differences are selected from the group consisting of at least one nucleotide deletion. substitution, including transition and transversion, or insertion. These differences may occur at the 5' or 3' terminal positions of the reference polynucleotide sequence or anywhere between these terminal positions, interspersed either individually among the nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence.
  • an average of up to 5 in every 100 of the nucleotides of the in the reference sequence may be deleted, substituted or inserted, or any combination thereof, as hereinbefore described.
  • a candidate polypeptide sequence having, for example, an Identity Index of 0.95 compared to a reference polypeptide sequence is identical to the reference sequence except that the polypeptide sequence may include an average of up to five differences per each 100 amino acids of the reference sequence. Such differences are selected from the group consisting of at least one amino acid deletion, substitution, including conservative and non-conservative substitution, or insertion. These differences may occur at the amino- or carboxy-terminal positions of the reference polypeptide sequence or anywhere between these terminal positions, interspersed either individually among the amino acids in the reference sequence or in one or more contiguous groups within the reference sequence.
  • an average of up to 5 in every 100 of the amino acids in the reference sequence may be deleted, substituted or inserted, or any combination thereof, as hereinbefore described.
  • n a is the number of nucleotide or amino acid differences
  • x a is the total number of nucleotides or amino acids in SEQ ID NO: 1 or SEQ ID NO:2, respectively
  • I is the Identity Inde .
  • • is the symbol for the multiplication operator, and in which any non-integer product of x a and I is rounded down to the nearest integer prior to subtracting it from x a .
  • “Homolog” is a generic term used in the art to indicate a polynucleotide or polypeptide sequence possessing a high degree of sequence relatedness to a reference sequence. Such relatedness may be quantified by determining the degree of identity and/or similarity between the two sequences as hereinbefore defined. Falling within this generic term are the terms “ortholog”, and “paralog”. "Ortholog” refers to a polynucleotide or polypeptide that is the functional equivalent of the polynucleotide or polypeptide in another species. "Paralog” refers to a polynucleotideor polypeptide that within the same species which is functionally similar.
  • Fusion protein refers to a protein encoded by two. often unrelated, fused genes or fragments thereof.
  • EP-A-0 464 533-A discloses fusion proteins comprising various portions of constant region of immunoglobulin molecules together with another human protein or part thereof.
  • employing an immunoglobulin Fc region as a part of a fusion protein is advantageous for use in therapy and diagnosis resulting in. for example, improved pharmacokinetic properties [see, e.g., EP-A 0232 262].

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

Cette invention, qui a trait à des polypeptides et à des polynucléotides GLYTLIKE ainsi qu'à des procédés de production de ces polypeptides et polynucléotides par des techniques de recombinaison, concerne également des méthodes d'utilisation des polypeptides et polynucléotides GLYTLIKE dans des épreuves diagnostiques.
PCT/GB1999/002909 1998-09-04 1999-09-03 Transporteur de glycine WO2000014221A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP99943113A EP1108020A1 (fr) 1998-09-04 1999-09-03 Transporteur de glycine
JP2000568965A JP2003513609A (ja) 1998-09-04 1999-09-03 グリシントランスポーター

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9819405.3 1998-09-04
GBGB9819405.3A GB9819405D0 (en) 1998-09-04 1998-09-04 Novel compounds

Publications (1)

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WO2000014221A1 true WO2000014221A1 (fr) 2000-03-16

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WO (1) WO2000014221A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018576A2 (fr) * 2000-08-28 2002-03-07 Diadexus, Inc. Compositions et methodes associees aux genes specifiques du poumon

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045446A1 (fr) * 1996-05-31 1997-12-04 Allelix Neuroscience Inc. Transporteur de glycine et cellules transfectees et leurs emplois

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045446A1 (fr) * 1996-05-31 1997-12-04 Allelix Neuroscience Inc. Transporteur de glycine et cellules transfectees et leurs emplois

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE EMBL NUCLEOTIDE SEQU 1 January 1900 (1900-01-01), XP002125018, Database accession no. Z96810 *
DATABASE EMBL NUCLEOTIDE SEQU 1 January 1900 (1900-01-01), XP002125019, Database accession no. AF151978 *
JENNIFER L. SLOAN ET AL.: "Cloning and functional expression of a human Na+ and Cl- dependent neutral and cationic amino acid transporter B0+", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 274, no. 34, 20 August 1999 (1999-08-20), MD US, pages 23740 - 23745, XP000863071 *
KIM K -M ET AL: "CLONING OF THE HUMAN GLYCINE TRANSPORTER TYPE 1: MOLECULAR AND PHARMACOLOGICAL CHARACTERIZATION OF NOVEL ISOFORM VARIANTS AND CHROMOSOMAL LOCALIZATION OF THE GENE IN THE HUMAN AND MOUSE GENOMES", MOLECULAR PHARMACOLOGY,US,BALTIMORE, MD, vol. 45, pages 608-617, XP002911694, ISSN: 0026-895X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018576A2 (fr) * 2000-08-28 2002-03-07 Diadexus, Inc. Compositions et methodes associees aux genes specifiques du poumon
WO2002018576A3 (fr) * 2000-08-28 2003-04-17 Diadexus Inc Compositions et methodes associees aux genes specifiques du poumon

Also Published As

Publication number Publication date
EP1108020A1 (fr) 2001-06-20
JP2003513609A (ja) 2003-04-15
GB9819405D0 (en) 1998-10-28

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