B12-asiaa: transkobalamiinit TCI eli haptokorriini , ravinnon corrinoidien tunnistaja

Transkobalamiinit (TC)  ovat kantajaproteiineja, jotka kiinnittyvät syanokobalamiiniin eli B₁₂-vitamiiniin ja kuljettavat ne solukalvon läpi. Niillä on merkitystä tutkittaessa B₁₂-vitamiinin puutetta, sillä jos transkobalamiiniin kiinnittyneen B12-vitamiinin osan holotranskobalamiinin (holoTC)  seerumipitoisuus pienenee, se voisi teoriassa merkitä B₁₂-puutteen kehittymisen varhaisvaihetta.^[1] Transkobalamiineja on I, II ja III, ja niistä transkobalamiini II on fysiologinen kuljettajaproteiini.^[2] Seerumin B₁₂-vitamiini on pääasiassa (80 %) sitoutuneena transkobalamiini I:een eikä siten ole elimistön käytettävissä. Vain transkobalamiini II:een sitoutunut vitamiini on elimistön käytettävissä. Transkobalamiini I:n puutos on harvinainen. B₁₂-vitamiinin määrä on siinä vähäinen, mutta megaloblastisen anemian muita löydöksiä tai oireita ei ilmene. Transkobalamiini II:n puutokseen liittyy jo lapsena alkava megaloblastinen anemia, jossa B₁₂-vitamiinipitoisuus on normaali.^[3

Engelsk definition

A group of carrier proteins which bind with VITAMIN B12 in the BLOOD and aid in its transport. Transcobalamin I migrates electrophoretically as a beta-globulin, while transcobalamins II and III migrate as alpha-globulins.

• TCI,  Haptocorrin, R-proteiini muodostuu syljessä ja sitouuu tiukasti kobalamiiniin kulkeutuen mahalaukkuun.  Cbl-R yhdisteenä. 

https://en.wikipedia.org/wiki/Haptocorrin

 Haptocorrin also known as transcobalamin-1 (TC-1) or cobalophilin is a transcobalamin protein that in humans is encoded by the TCN1 gene.^[3] The essential function of haptocorrin is protection of the acid-sensitive vitamin B₁₂ while it moves through the stomach.

Function

Haptocorrin (HC), also commonly known as the R-protein, or the R-factor, or previously referred to as transcobalamin I, is a unique glycoprotein produced by the salivary glands of the oral cavity, in response to ingestion of food. This protein binds strongly to vitamin B₁₂ in what is an intricate and necessary mechanism to protect this vitamin from the acidic environment of the stomach.^[4]:44
 Despite its vital role however, vitamin B₁₂ is structurally very sensitive to the hydrochloric acid found in the stomach secretions, and easily denatures in that environment before it has a chance to be absorbed by the small intestine. Found in fresh animal products (such as liver), vitamin B₁₂ attaches haptocorrin, which has a high affinity for its molecular structure.^[5] Coupled together vitamin B₁₂ and haptocorrin create a complex. This Haptocorrin-B₁₂ complex is impervious to the insult of the stomach acid, and passes on via the pylorus to the duodenum.

 In the duodenum pancreatic proteases (a component of pancreatic juice) cleave haptocorrin, releasing vitamin B₁₂ in its free form.


The same cells in the stomach that produce gastric hydrochloric acid, the parietal cells, also produce a molecule called the intrinsic factor (IF), which binds the B₁₂ after its release from haptocorrin by digestion, and without which only 1% of vitamin B₁₂ is absorbed.

 Intrinsic factor (IF) is a glycoprotein, with a molecular weight of 45 kDa. In the duodenum, the free vitamin B₁₂ attaches to the intrinsic factor (IF) to create a vitamin B₁₂-IF complex. This complex then travels through the small bowel and reaches the terminal tertiary portion of the small intestine, called the ileum. The ileum is the longest of all portions of the small intestine, and has on its surface specialized receptors called cubilin receptors, that identify the B₁₂-IF complexes and take them up into the circulation via endocytosis mediated absorption.^[6]

In short, the essential function of haptocorrin is protection of the acid-sensitive vitamin B₁₂ while it moves through the stomach. Haptocorrin also circulates and binds approximately 80% of circulating B₁₂, rendering it unavailable for cellular delivery by transcobalamin II.^[7]

 

•  Siis  haptokorriini toimii kuin kaitsijaproteiini tavallaan päätarkoituksena saada pyydystettyä   Cbl kun sitä ilmenee ruoassa  ja  johtaa Cbl   mahdolliseen  kohtaan jsoas se voi siirtyä  denaturoitumisen välttäen  "intrinsic factorille"
  Geeni TCNI, Kr.11q12.1. 

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  2. Role of serum holotranscobalamin (holoTC) in the diagnosis of patients with low serum cobalamin. Comparison with methylmalonic acid and homocysteine. Remacha AF, et al. Ann Hematol, 2014 Apr. PMID 24057896
  3. Structural basis for universal corrinoid recognition by the cobalamin transport protein haptocorrin. Furger E, et al. J Biol Chem, 2013 Aug 30. PMID 23846701, Free PMC Article
  4. Elevated vitamin B₁₂ levels in autoimmune lymphoproliferative syndrome attributable to elevated haptocorrin in lymphocytes. Bowen RA, et al. Clin Biochem, 2012 Apr. PMID 22306884, Free PMC Article
  5. Genomic mutations associated with mild and severe deficiencies of transcobalamin I (haptocorrin) that cause mildly and severely low serum cobalamin levels. Carmel R, et al. Br J Haematol, 2009 Nov. PMID 19686235

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  See citations in PubMed for homologs of this gene provided by HomoloGene

  GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

  1. The variant rs526934 from the TCN1 gene was associated with an increased risk of developing gastric cancer.
  2. Levels of holotranscobalamin are decreased patients with cobalamin deficiency.
  3. Structural basis for universal corrinoid recognition by the cobalamin transport protein haptocorrin.
  4. TCN1 gene expression implicates disease progression in patient with middle ear cholesteatoma.
  5. comparison of human and rainbow trout cobalamin-binding protein
  6. Elevated concentrations of B(12) found in autoimmune lymphoproliferative syndrome patients were due to increased lymphocyte expression of haptocorrin.
  7. Stromal expression of KRT15, TCN1, and HOXB13 was significantly correlated with tumor grade, stromal hypercellularity, mitotic activity and microscopic borders.
  8. Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
  9. two novel mutations, each causing a premature stop codon - a genetic basis for TC I deficiency
  10. Observational study of gene-disease association, gene-gene interaction, gene-environment interaction, and genetic testing. (HuGE Navigator)

 

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J Biol Chem. 2013 Aug 30;288(35):25466-76. doi: 10.1074/jbc.M113.483271. Epub 2013 Jul 11.

Structural basis for universal corrinoid recognition by the cobalamin transport protein haptocorrin.

Furger E¹, Frei DC, Schibli R, Fischer E, Prota AE.

Abstract

Cobalamin (Cbl; vitamin B12) is an essential micronutrient synthesized only by bacteria. Mammals have developed a sophisticated uptake system to capture the vitamin from the diet. Cbl transport is mediated by three transport proteins:

•  transcobalamin, 
• intrinsic factor, 
• and haptocorrin (HC).

 All three proteins have a similar overall structure but a different selectivity for corrinoids. Here, we present the crystal structures of human HC in complex with cyanocobalamin and cobinamide at 2.35 and 3.0 Å resolution, respectively. The structures reveal that many of the interactions with the corrin ring are conserved among the human Cbl transporters. However, the non-conserved residues Asn-120, Arg-357, and Asn-373 form distinct interactions allowing for stabilization of corrinoids other than Cbl. A central binding motif forms interactions with the e- and f-side chains of the corrin ring and is conserved in corrinoid-binding proteins of other species. In addition, the α- and β-domains of HC form several unique interdomain contacts and have a higher shape complementarity than those of intrinsic factor and transcobalamin. The stabilization of ligands by all of these interactions is reflected in higher melting temperatures of the protein-ligand complexes. Our structural analysis offers fundamental insights into the unique binding behavior of HC and completes the picture of Cbl interaction with its three transport proteins.

KEYWORDS:

Biosynthesis; Cobalamin; Cobinamide; Cofactors; Corrinoids; Crystal Structure; Haptocorrin; Metabolism; Nutrition; Vitamins

PMID:

23846701

PMCID:

PMC3757208

DOI:

10.1074/jbc.M113.483271

[Indexed for MEDLINE]

Free PMC Article

ON TÄMÄ HAPTOKORIINIKIN  AIKA ISO AMINOHAPPOPEPTIDI. 433 AMINOHAPPOA.
Siis ei riitä B12-vitamiinin puutteen hoitoon pelkästään pikkuinen pilleri B12-vitamiinia. vaan tarvitaan kunnon energiaa ja proteiinipitoista  ruokaa, että näitä kuljettajiakin ja tunnistajiakin löytyy.
https://www.ncbi.nlm.nih.gov/protein/NP_001053.2 
On luonnollsita että proteiinin puutteessa ja ruokamäärien vähetessä tulee B12 puute kaikkine kurjine seuraamuksineen.  Eläimellä ei esiinny B12 puutetta.  Se on sivistyksen huipun tauti, siis ihmisen tauti.

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