Details for: MTHFD1

Gene ID: 4522

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: MTHFD1

Ensembl ID: ENSG00000100714

Description: methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • centrilobular region hepatocyte CL0019029
    CSI 9.18
    rCSI 23.94%
    PRS 87.37
  • vascular leptomeningeal cell CL4023051
    CSI 7.1
    rCSI 12.45%
    PRS 88.07
  • common myeloid progenitor CL0000049
    CSI 7.08
    rCSI 5.73%
    PRS 92.31
  • hepatocyte CL0000182
    CSI 5.85
    rCSI 10.47%
    PRS 89.92
  • Kupffer cell CL0000091
    CSI 5.21
    rCSI 11.91%
    PRS 92.26
  • astrocyte of the cerebral cortex CL0002605
    CSI 4.97
    rCSI 11.15%
    PRS 79.63
  • hepatic stellate cell CL0000632
    CSI 4.41
    rCSI 16.51%
    PRS 87.31
  • midzonal region hepatocyte CL0019028
    CSI 3.8
    rCSI 8.92%
    PRS 89
  • neural crest cell CL0011012
    CSI 3.13
    rCSI 2.47%
    PRS 84.88
  • promyelocyte CL0000836
    CSI 3.06
    rCSI 4.42%
    PRS 93.13
  • melanocyte CL0000148
    CSI 3.03
    rCSI 2.24%
    PRS 88.03
  • bronchus fibroblast of lung CL2000093
    CSI 3
    rCSI 2.43%
    PRS 90.67
  • alveolar type 1 fibroblast cell CL4028004
    CSI 2.97
    rCSI 3.26%
    PRS 92.8
  • choroid plexus epithelial cell CL0000706
    CSI 2.87
    rCSI 4.71%
    PRS 84.91
  • kidney loop of Henle thin descending limb epithelial cell CL1001111
    CSI 2.81
    rCSI 3.98%
    PRS 89.31
  • hematopoietic stem cell CL0000037
    CSI 2.8
    rCSI 1.86%
    PRS 92.67
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.67
    rCSI 2.32%
    PRS 93.26
  • stem cell CL0000034
    CSI 2.54
    rCSI 2.45%
    PRS 87.49
  • colon epithelial cell CL0011108
    CSI 2.48
    rCSI 2.59%
    PRS 89.16
  • plasmablast CL0000980
    CSI 2.47
    rCSI 1.94%
    PRS 93.33
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.45
    rCSI 2.21%
    PRS 90.09
  • adipocyte CL0000136
    CSI 2.35
    rCSI 3.02%
    PRS 83.83
  • VIP GABAergic cortical interneuron CL4023016
    CSI 2.31
    rCSI 2.76%
    PRS 79.27
  • placental villous trophoblast CL2000060
    CSI 2.27
    rCSI 3.51%
    PRS 89.53
  • myeloid leukocyte CL0000766
    CSI 2.26
    rCSI 2.08%
    PRS 92.31
  • periportal region hepatocyte CL0019026
    CSI 2.25
    rCSI 8.77%
    PRS 88.24
  • Mueller cell CL0000636
    CSI 2.2
    rCSI 5.03%
    PRS 85.33
  • epithelial cell CL0000066
    CSI 2.19
    rCSI 3.36%
    PRS 80
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.1
    rCSI 2.7%
    PRS 80.35
  • retinal bipolar neuron CL0000748
    CSI 2.01
    rCSI 3.77%
    PRS 83.56
  • transit amplifying cell of colon CL0009011
    CSI 1.97
    rCSI 2.32%
    PRS 91.23
  • radial glial cell CL0000681
    CSI 1.95
    rCSI 2.71%
    PRS 89.8
  • regular ventricular cardiac myocyte CL0002131
    CSI 1.88
    rCSI 11.76%
    PRS 85.54
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 1.87
    rCSI 2.32%
    PRS 77.05
  • neuroblast (sensu Vertebrata) CL0000031
    CSI 1.82
    rCSI 2.34%
    PRS 87.78
  • direct pathway medium spiny neuron CL4023026
    CSI 1.81
    rCSI 43.22%
    PRS 77.01
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.77
    rCSI 42.67%
    PRS 77.15
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 1.76
    rCSI 2.03%
    PRS 84.27
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.67
    rCSI 2.96%
    PRS 78.66
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.46
    rCSI 2.35%
    PRS 80.14
  • glioblast CL0000030
    CSI 1.44
    rCSI 2.3%
    PRS 84.27
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.38
    rCSI 2.32%
    PRS 79.24
  • transit amplifying cell of small intestine CL0009012
    CSI 1.33
    rCSI 5.83%
    PRS 94.23
  • club cell CL0000158
    CSI 1.31
    rCSI 1.92%
    PRS 87.27
  • erythroid progenitor cell CL0000038
    CSI 1.29
    rCSI 7.42%
    PRS 93.08
  • cardiac muscle cell CL0000746
    CSI 1.19
    rCSI 1.71%
    PRS 83.91
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 1.16
    rCSI 3.12%
    PRS 93.15
  • large pre-B-II cell CL0000957
    CSI 1.11
    rCSI 3.16%
    PRS 91.25
  • erythroid lineage cell CL0000764
    CSI 1.04
    rCSI 6.66%
    PRS 93.54
  • erythroblast CL0000765
    CSI 0.9
    rCSI 2.39%
    PRS 92.03
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 0.82
    rCSI 2%
    PRS 77.08
  • retinal ganglion cell CL0000740
    CSI 0.82
    rCSI 1.8%
    PRS 81.58
  • primitive red blood cell CL0002355
    CSI 0.79
    rCSI 4.25%
    PRS 92.61
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 0.77
    rCSI 2.93%
    PRS 79.43
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.71
    rCSI 2.56%
    PRS 77.28
  • myeloid lineage restricted progenitor cell CL0000839
    CSI 0.63
    rCSI 3.25%
    PRS 97.47
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.63
    rCSI 1.96%
    PRS 80.54
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 0.62
    rCSI 1.94%
    PRS 82.17
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 0.4
    rCSI 2.33%
    PRS 79.67
  • blood vessel smooth muscle cell CL0019018
    CSI 0.38
    rCSI 3.13%
    PRS 89
  • central nervous system neuron CL2000029
    CSI 0.3
    rCSI 2.21%
    PRS 83.71

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [MTHFD1](/details-gene/4522) (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1) is a protein-coding gene located on chromosome 14q23.3. It encodes a crucial trifunctional enzyme that catalyzes three sequential reactions in the cytoplasmic one-carbon folate metabolic pathway. This pathway is essential for the *de novo* synthesis of purines, thymidine, and for the remethylation of homocysteine to methionine ([Link](https://pubmed.ncbi.nlm.nih.gov/3053686/)). Reflecting its central role in metabolism, [MTHFD1](/details-gene/4522) shows significant expression in highly proliferative and metabolically active cells, most notably in various types of [hepatocytes](/details-cell/CL0000182) within the liver and in hematopoietic progenitors such as the [common myeloid progenitor](/details-cell/CL0000049). Its function is clinically significant, with genetic variations linked to conditions such as neural tube defects ([OMIM:601634](https://omim.org/entry/601634)). ## Cellular Roles and Expression Landscape The expression profile of [MTHFD1](/details-gene/4522) highlights its fundamental importance in cellular biosynthesis and proliferation. **Overall**, the gene's highest significance is observed in the liver, with top expression in [centrilobular region hepatocytes](/details-cell/CL0019029) (CSI: 9.18), general [hepatocytes](/details-cell/CL0000182) (CSI: 5.85), and [midzonal region hepatocytes](/details-cell/CL0019028) (CSI: 3.80). This prominent expression pattern is consistent with the liver's central role as the primary site for one-carbon metabolism, including purine and methionine synthesis. Other liver-resident cells, such as [Kupffer cells](/details-cell/CL0000091) (CSI: 5.21) and [hepatic stellate cells](/details-cell/CL0000632) (CSI: 4.41), also show high significance, underscoring the gene's broad importance within the hepatic microenvironment. Beyond the liver, [MTHFD1](/details-gene/4522) is a key gene in hematopoietic development, evidenced by its high significance in [common myeloid progenitors](/details-cell/CL0000049) (CSI: 7.08) and [promyelocytes](/details-cell/CL0000836) (CSI: 3.06). This suggests a critical requirement for [MTHFD1](/details-gene/4522)-mediated nucleotide synthesis to support the rapid cell division characteristic of blood cell formation. Furthermore, [MTHFD1](/details-gene/4522) expression is notable in various neural and developmental cell types, including [vascular leptomeningeal cells](/details-cell/CL4023051) (CSI: 7.10), [astrocytes of the cerebral cortex](/details-cell/CL0002605) (CSI: 4.97), and [neural crest cells](/details-cell/CL0011012) (CSI: 3.13). This aligns with its established role in embryonic development, particularly the formation of the nervous system. ## Pathways and Molecular Function [MTHFD1](/details-gene/4522) is a cornerstone of one-carbon metabolism. Its trifunctional nature encompasses three distinct enzymatic activities: *methylenetetrahydrofolate dehydrogenase* ([GO:0004486](/https://www.ebi.ac.uk/QuickGO/term/GO:0004486)), *methenyltetrahydrofolate cyclohydrolase* ([GO:0004477](/https://www.ebi.ac.uk/QuickGO/term/GO:0004477)), and *formate-tetrahydrofolate ligase* ([GO:0004329](/https://www.ebi.ac.uk/QuickGO/term/GO:0004329)). These activities are integral to the biological process of *tetrahydrofolate interconversion* ([GO:0035999](/https://www.ebi.ac.uk/QuickGO/term/GO:0035999)) within the cytosol ([GO:0005829](/https://www.ebi.ac.uk/QuickGO/term/GO:0005829)). The one-carbon units generated by [MTHFD1](/details-gene/4522) are vital substrates for numerous downstream pathways. Chief among these are the *purine nucleotide biosynthetic process* ([GO:0006164](/https://www.ebi.ac.uk/QuickGO/term/GO:0006164)) and the *methionine metabolic process* ([GO:0006555](/https://www.ebi.ac.uk/QuickGO/term/GO:0006555)). This directly connects the gene's function to DNA replication, RNA synthesis, and cellular methylation reactions. This central metabolic role is comprehensively captured by its annotation in Reactome pathways such as *Metabolism of folate and pterines* ([R-HSA-196757](https://reactome.org/content/detail/R-HSA-196757)). The gene's involvement in critical developmental processes, including *neural tube closure* ([GO:0001843](/https://www.ebi.ac.uk/QuickGO/term/GO:0001843)), *embryonic neurocranium morphogenesis* ([GO:0048702](/https://www.ebi.ac.uk/QuickGO/term/GO:0048702)), and *heart development* ([GO:0007507](/https://www.ebi.ac.uk/QuickGO/term/GO:0007507)), underscores why disruptions in its function can lead to severe congenital abnormalities. ## Research Directions The central role of [MTHFD1](/details-gene/4522) in providing one-carbon units for nucleotide synthesis makes it a critical node for rapidly proliferating cells, both in normal physiology and in disease. This presents several avenues for future research. **Proposed Hypotheses:** 1. Given its high significance in [common myeloid progenitors](/details-cell/CL0000049), it is hypothesized that cancer cells in acute myeloid leukemia (AML) exhibit heightened dependency on [MTHFD1](/details-gene/4522) for survival and proliferation compared to their healthy counterparts. 2. The pronounced expression of [MTHFD1](/details-gene/4522) across multiple liver cell types, including [hepatocytes](/details-cell/CL0000182) and [hepatic stellate cells](/details-cell/CL0000632), suggests that dysregulation of [MTHFD1](/details-gene/4522) activity may contribute to the pathogenesis of liver fibrosis by altering methylation patterns and metabolic flux, thereby promoting stellate cell activation. 3. The established link to neural tube defects suggests that maternal nutritional status (e.g., folate levels) may interact with specific low-activity [MTHFD1](/details-gene/4522) polymorphisms to significantly increase the risk of these developmental anomalies in offspring. **Experimental Approach:** To test hypothesis 1, one could utilize a panel of AML cell lines and primary patient samples. The dependency on [MTHFD1](/details-gene/4522) could be assessed by CRISPR-Cas9-mediated gene knockout or shRNA knockdown, followed by cell viability and proliferation assays. A parallel experiment using a specific small-molecule inhibitor of [MTHFD1](/details-gene/4522) would validate this dependency. Furthermore, metabolic flux analysis using stable isotope tracers (e.g., ¹³C-serine) could be employed to directly measure the impact of [MTHFD1](/details-gene/4522) inhibition on the *de novo* purine synthesis pathway in AML cells versus healthy hematopoietic stem and progenitor cells. **Therapeutic Potential:** [MTHFD1](/details-gene/4522) is a compelling therapeutic target, primarily for cancer. As a cytoplasmic enzyme, it is amenable to small-molecule inhibition. The therapeutic strategy would be **inhibition** to starve cancer cells of the nucleotides required for their rapid growth. Several inhibitors targeting the dehydrogenase/cyclohydrolase domain of [MTHFD1](/details-gene/4522) are in preclinical development. The primary challenge is potential on-target toxicity in healthy, highly proliferative tissues like the bone marrow and gastrointestinal tract. Therefore, identifying specific cancer types that are uniquely dependent on the cytoplasmic folate pathway, or developing strategies for targeted drug delivery, will be critical for clinical translation.

Genular Protein ID: 3552543250

Symbol: C1TC_HUMAN

Name: C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed

UniProtKB Accession Codes:

P11586 A0A024R652 A0A384N5Y3 B2R5Y2 G3V2B8 Q86VC9 Q9BVP5

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 4 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CPTAC 2 CTD 1 ChEBI 17 ChEMBL 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 5 EC 3 EMBL 9 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 26 Gene3D 5 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HAMAP 2 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 9 KEGG 1 MANE-Select 1 MIM 7 MINT 1 MalaCards 1 MassIVE 1 MetOSite 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 7 PDBsum 7 PIR 1 PRINTS 1 PRO 1 PROSITE 4 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 REPRODUCTION-2DPAGE 1 RNAct 1 Reactome 1 RefSeq 1 Rhea 4 SIGNOR 1 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 3053686

Title: Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase.

PubMed ID: 3053686

DOI: 10.1016/s0021-9258(18)37540-9

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 12508121

Title: The DNA sequence and analysis of human chromosome 14.

PubMed ID: 12508121

DOI: 10.1038/nature01348

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 12665801

Title: Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides.

PubMed ID: 12665801

DOI: 10.1038/nbt810

PubMed ID: 1881876

Title: Expression of active domains of a human folate-dependent trifunctional enzyme in Escherichia coli.

PubMed ID: 1881876

DOI: 10.1093/protein/4.4.493

PubMed ID: 14654843

Title: Proteomic characterization of the human centrosome by protein correlation profiling.

PubMed ID: 14654843

DOI: 10.1038/nature02166

PubMed ID: 19413330

Title: Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.

PubMed ID: 19413330

DOI: 10.1021/ac9004309

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 22223895

Title: Comparative large-scale characterisation of plant vs. mammal proteins reveals similar and idiosyncratic N-alpha acetylation features.

PubMed ID: 22223895

DOI: 10.1074/mcp.m111.015131

PubMed ID: 22814378

Title: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB.

PubMed ID: 22814378

DOI: 10.1073/pnas.1210303109

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 25944712

Title: N-terminome analysis of the human mitochondrial proteome.

PubMed ID: 25944712

DOI: 10.1002/pmic.201400617

PubMed ID: 9519408

Title: The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5-A resolution.

PubMed ID: 9519408

DOI: 10.1016/s0969-2126(98)00019-7

PubMed ID: 10828945

Title: Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase.

PubMed ID: 10828945

DOI: 10.1021/bi992734y

PubMed ID: 9611072

Title: Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects.

PubMed ID: 9611072

DOI: 10.1111/j.1399-0004.1998.tb02658.x

PubMed ID: 12384833

Title: A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group.

PubMed ID: 12384833

DOI: 10.1086/344213

PubMed ID: 16552426

Title: Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population.

PubMed ID: 16552426

DOI: 10.1038/sj.ejhg.5201603

PubMed ID: 17000706

Title: Search for low penetrance alleles for colorectal cancer through a scan of 1467 non-synonymous SNPs in 2575 cases and 2707 controls with validation by kin-cohort analysis of 14 704 first-degree relatives.

PubMed ID: 17000706

DOI: 10.1093/hmg/ddl401

PubMed ID: 18767138

Title: The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects.

PubMed ID: 18767138

DOI: 10.1002/humu.20830

PubMed ID: 21813566

Title: Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband.

PubMed ID: 21813566

DOI: 10.1136/jmedgenet-2011-100286

PubMed ID: 25633902

Title: Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.

PubMed ID: 25633902

DOI: 10.1007/s10545-015-9810-3

PubMed ID: 27707659

Title: Precision molecular diagnosis defines specific therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 deficiency.

PubMed ID: 27707659

DOI: 10.1016/j.jaip.2016.07.014

Sequence Information:

  • Length: 935
  • Mass: 101531
  • Checksum: B834DB504BC1869A
  • Sequence:
    • MAPAEILNGK EISAQIRARL KNQVTQLKEQ VPGFTPRLAI LQVGNRDDSN LYINVKLKAA 
EEIGIKATHI KLPRTTTESE VMKYITSLNE DSTVHGFLVQ LPLDSENSIN TEEVINAIAP 
EKDVDGLTSI NAGKLARGDL NDCFIPCTPK GCLELIKETG VPIAGRHAVV VGRSKIVGAP 
MHDLLLWNNA TVTTCHSKTA HLDEEVNKGD ILVVATGQPE MVKGEWIKPG AIVIDCGINY 
VPDDKKPNGR KVVGDVAYDE AKERASFITP VPGGVGPMTV AMLMQSTVES AKRFLEKFKP 
GKWMIQYNNL NLKTPVPSDI DISRSCKPKP IGKLAREIGL LSEEVELYGE TKAKVLLSAL 
ERLKHRPDGK YVVVTGITPT PLGEGKSTTT IGLVQALGAH LYQNVFACVR QPSQGPTFGI 
KGGAAGGGYS QVIPMEEFNL HLTGDIHAIT AANNLVAAAI DARIFHELTQ TDKALFNRLV 
PSVNGVRRFS DIQIRRLKRL GIEKTDPTTL TDEEINRFAR LDIDPETITW QRVLDTNDRF 
LRKITIGQAP TEKGHTRTAQ FDISVASEIM AVLALTTSLE DMRERLGKMV VASSKKGEPV 
SAEDLGVSGA LTVLMKDAIK PNLMQTLEGT PVFVHAGPFA NIAHGNSSII ADRIALKLVG 
PEGFVVTEAG FGADIGMEKF FNIKCRYSGL CPHVVVLVAT VRALKMHGGG PTVTAGLPLP 
KAYIQENLEL VEKGFSNLKK QIENARMFGI PVVVAVNAFK TDTESELDLI SRLSREHGAF 
DAVKCTHWAE GGKGALALAQ AVQRAAQAPS SFQLLYDLKL PVEDKIRIIA QKIYGADDIE 
LLPEAQHKAE VYTKQGFGNL PICMAKTHLS LSHNPEQKGV PTGFILPIRD IRASVGAGFL 
YPLVGTMSTM PGLPTRPCFY DIDLDPETEQ VNGLF