MEPRIINIT, Mitä ne ovat. kalvoon sitoutuneita astasiineja! / metalloproteinaasiryhmkää metsinkiinien suoerperheestä)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650038/
Tämä ihmisen TRIM37 jossa on  peptidihännäss MATH domeeni eli Mepriini ja TRAF-  homologidomeeni9 on peroxisomaalinen proteiini ja jos MATHdomeenissa on mutaatio, siitäseuraa että kokoTRUIM37  sijoittautuu muualle kuin peroxisomiin. 
Muita trimejä ei´n löytänyt joissa olisi tämä mepriini- tunnusmerkki.  olisko peroksisomit  tulleet  ihmiseen jostain sieltä ihan "korallien ajoista" ?
Täytyy katsoa mistäniitä tuli ihmiseen.

Tässä linkissä on hyviä kaavoja metsinkiineistä. 

ihmisen Meprin 1A alfa ja beta
https://www.ncbi.nlm.nih.gov/protein/Q16819 
https://www.ncbi.nlm.nih.gov/protein/XP_011524315.1 

 Biochem. J. (2013)450, 253–264 (Printed in Great Britain)doi:10.1042/BJ20121751253
 REVIEW ARTICLE The metalloproteases meprinα and meprinβ: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis 
Claudia BRODER and Christoph BECKER-PAULY

The  metalloproteases meprinα and meprinβ exhibit structural and functional features that are unique among all extracellular proteases. Although meprins were discovered more than 30 years ago, their precise substrates and physiological roles have been elusive. Both enzymes were originally found to be highly expressed in kidney and intestine, which focused research on these particular tissues and associated pathologies. Only recently it has become evident that meprins exhibit a much broader expression pattern, implicating functions in angiogenesis, cancer, inflammation, fibrosis and neurodegenerative diseases. Different animal models, as well as proteomics approaches for the identification of protease substrates, have helped to reveal more precise molecular signalling events mediated by meprin activity, such as activation and release of pro-inflammatory cytokines. APP (amyloid precursor protein) is cleaved by meprinβ in vivo, reminiscent of the β-secretase BACE1 (β-site APP-cleaving enzyme 1). The subsequent release of Aβ(amyloidβ)
peptides is thought to be the major cause of the neurodegenerative Alzheimer’s disease. On the other hand, ADAM10 (a disintegrin and metalloprotease domain 10), which is the constitutiveα-secretase, was shown to be activated by meprinβ, which is it self shed from the cell surface by ADAM10.
 In skin, both meprins are overexpressed in fibrotic tumours, characterized by massive accumulation of fibrillar collagens. Indeed, procollagen III is processed to its mature form by meprinα and meprinβ,an essential step in collagen fibril assembly. The recently solved crystal structure of meprinβ and the unique cleavage specificity of these proteases identified by proteomics will help to generate specific inhibitors that could be used as therapeutics to target meprins under certain pathological conditions .Key words: cancer, fibrosis, inflammation, meprin, metalloprotease, neurodegeneration, proteomics.

 Structure length function
Meprins are complex and highly glycosylated multi-domainenzymes that require post-translational modifications to reach fullactivity. They are expressed as proteolytically inactive zymogens that require the removal of their N-terminal propeptides by otherproteases. Several serine proteases have been identified as doingthis job [30–34], e.g. members of the tissue KLKs (kallikrein-related peptidases).Meprins belong to the astacin family of metalloproteases,comprising only six members in humans [35]. These enzymes are characterized by a conserved zinc-binding motif(HExxHxxGxxHxxxRxDR) and by a sequence in close proximity to the active-site cleft, the so called Met-turn, that includes a tyrosine residue as a fifth zinc ligand. Within the astacin family,meprins exhibit a unique domain composition. Human meprinα and β, encoded on chromosomes 6 and8 respectively, comprise an N-terminal signal peptide directing the polypeptide chain to the endoplasmic reticulum, an N-terminal propeptide, an astacin-like protease domain, a MAM(meprin A5 protein tyrosine phosphataseμ) domain and a TRAF(tumour-necrosis-factor-receptor-associated factor) domain, both of which are known to mediate protein–protein interactions, anEGF (epidermal growth factor)-like domain, a transmembranedomain, and a C-terminal cytosolic tail (Figure 1A)

 Mistä niit pre-peroxisomeja olisi tullut?
(Ehkä jokin niistä Cnidarioista hienolla injektiotekniikallaan on antanut "kykyjä"  monisoluisiin organismeihin, joisa kiertää veri ja on muutakin ravinnetta.  Siitä ajasta olisi peroxisomeihin jäänyt se  meoprin-MATH-pätkä TRIm37:ään kai.
 https://onlinelibrary.wiley.com/doi/full/10.1002/bies.201700050
 

Metzinkiinisuperperhe, alaperhe Astasiinit: Alaryhmä Mepriinit , Mepriini beta

Meprin beta
https://www.ncbi.nlm.nih.gov/pubmed/31604820

J Biol Chem. 2019 Nov 22;294(47):17768-17776. doi: 10.1074/jbc.RA119.008310. Epub 2019 Oct 11.

Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β.

Menon PK¹, Koistinen NA¹, Iverfeldt K¹, Ström AL².

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of β-amyloid (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP), and aberrant posttranslational modifications of APP can alter APP processing and increase Aβ generation. In the AD brain, seven different residues, including Ser-675 (APP⁶⁹⁵ numbering) in the APP cytoplasmic domain has been found to be phosphorylated. Here, we show that expression of a phosphomimetic variant of Ser-675 in APP (APP-S675E), in human neuroblastoma SK-N-AS cells, reduces secretion of the soluble APP ectodomain (sAPPα), even though the total plasma membrane level of APP was unchanged compared with APP levels in cells expressing APPwt or APP-S675A. Moreover, the level of an alternative larger C-terminal fragment (CTF) increased in the APP-S675E cells, whereas the CTF form that was most abundant in cells expressing APPwt or APP-S675A decreased in the APP-S675E cells. Upon siRNA-mediated knockdown of the astacin metalloprotease meprin β, the levels of the alternative CTF decreased and the CTF ratio was restored back to APPwt levels. Our findings suggest that APP-Ser-675 phosphorylation alters the balance of APP processing, increasing meprin β-mediated and decreasing α-secretase-mediated processing of APP at the plasma membrane. As meprin β cleavage of APP has been shown to result in formation of highly aggregation-prone, truncated Aβ2-40/42 peptides, enhanced APP processing by this enzyme could contribute to AD pathology. We propose that it would be of interest to clarify in future studies how APP-Ser-675 phosphorylation promotes meprin β-mediated APP cleavage.

© 2019 Menon et al.

KEYWORDS:

ADAM; APP-CTF; Alzheimer's disease; amyloid precursor protein (APP); amyloid-beta (Aβ); meprin β; neurodegeneration; proteolytic processing; β-secretase 1 (BACE1)

PMID:

31604820

PMCID:

PMC6879340

DOI:

10.1074/jbc.RA119.008310


Tässä katson TRIM37, jolla on domeenit RBC ja MATH ( (Meprin and TRAF Homolog). Kor. 17  sijainti.
Mitenkähän tämä toimii normaalisti?  Se vaikuttaa radioreistenssiä, joka havaitaan  silloin kun kätyetään cisplatiinia tuumoriin..

https://www.ncbi.nlm.nih.gov/pubmed/30254148 
 Conserved Domains (4) summary

smart00502
Location:132 → 254

BBC; B-Box C-terminal domain

cd00162
Location:15 → 58

RING; RING-finger (Really Interesting New Gene) domain, a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc; defined by the 'cross-brace' motif C-X2-C-X(9-39)-C-X(1-3)- H-X(2-3)-(N/C/H)-X2-C-X(4-48)C-X2-C; probably involved in ...

cd03773
Location:273 → 406

MATH_TRIM37; Tripartite motif containing protein 37 (TRIM37) family, MATH domain; TRIM37 is a peroxisomal protein and is a member of the tripartite motif (TRIM) protein subfamily, also known as the RING-B-box-coiled-coil (RBCC) subfamily of zinc-finger proteins. ...https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=239742
 The MATH domain of TRIM37 has been shown to interact with the TRAF domain of six known TRAFs in vitro, however, it is unclear whether this is physiologically relevant. Eleven TRIM37 mutations have been associated with Mulibrey nanism so far. One mutation, Gly322Val, is located in the MATH domain and is the only mutation that does not affect the length of the protein. It results in the incorrect subcellular localization of TRIM37.

pfam00643
Location:90 → 132

zf-B_box;

Pseudomonas serralysin

https://www.ncbi.nlm.nih.gov/pubmed/31933178
https://www.ebi.ac.uk/interpro/entry/InterPro/IPR011049/

J Cyst Fibros. 2019 Oct 31. pii: S1569-1993(19)30916-6. doi: 10.1016/j.jcf.2019.10.009. [Epub ahead of print]  Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al.

Olesen HV¹, Drevinek P², Gulmans VA³, Hatziagorou E⁴, Jung A⁵, Mei-Zahav M⁶, Stojnic N⁷, Thomas M⁸, Zolin A⁹; ECFSPR Steering Group. Abstract

Cystic fibrosis related diabetes (CFRD) has implications for morbidity and mortality with several risk factors identified. We studied the epidemiology of CFRD in the large dataset of the European Cystic Fibrosis Society Patient registry.
Data on CF patients were investigated for the prevalence of CFRD as well as for any association with suggested risk factors and effects.
CFRD increased by approximately ten percentage points every decade from ten years of age. Prevalence was higher in females in the younger age groups. CFRD was associated with severe CF genotypes (OR = 3.11, 95%CI: 2.77-3.48), pancreatic insufficiency (OR = 1.46, 95%CI: 1.39-1.53) and female gender (OR = 1.28, 95%CI: 1.21-1.34). Patients with CFRD had higher odds of being chronically infected with Pseudomonas aeruginosa, Burkholderia cepacia complex and Stenotrophomonas maltophilia than patients without CFRD, higher odds of having FEV1% of predicted <40 1.15-1.34="" 1.24="" 1.70-1.94="" 1.82="" 95="" and="" bmi="" cfrd="" having="" higher="" odds="" of="" p="" patients="" sds="" than="" without="">  CONCLUSIONS:
Severe genotype, pancreatic insufficiency and female gender remain considerable intrinsic risk factors for early acquisition of CFRD. CFRD is associated with infections, lower lung function and poor nutritional status. Early diagnosis and aggressive treatment of CFRD are more important than ever with increasing life span.

Diabetes on Egyptin tavallisin tauti. Kansanlääkevaikutuksesta (2019) : Proteus ja diabetes.

PubMEd : hakusana"Proteus, Diabetes"
Eräiä   vastauksia: 
(1) Curr Pharm Biotechnol. 2019;20(7):595-604. doi: 10.2174/1389201020666190613161212.

Antibacterial and Potential Antidiabetic Activities of Flavone C-glycosides Isolated from Beta vulgaris Subspecies cicla L. var. Flavescens (Amaranthaceae) Cultivated in Egypt.

Mohammed HS¹, Abdel-Aziz MM², Abu-Baker MS¹, Saad AM³, Mohamed MA³, Ghareeb MA³.

Author information

Abstract

BACKGROUND:
Diabetes mellitus is the most common disease in Egypt. In this context, Beta vulgaris subspecies cicla L. var. flavescens is an edible plant that has been used in traditional medicine as a therapy for treating some diseases.
OBJECTIVES:
The current study was performed to evaluate the antibacterial and potential anti-diabetic activities of different extracts and isolated flavone C-glycoside compounds isolated from Beta vulgaris subspecies cicla L. var. flavescens leaves.
METHODS:
Phytochemical investigation of n-butanol extract led to the isolation of five phytoconstituents. Their structures were determined by spectroscopic tools, including 1D-NMR (1H- & 13C-NMR) and 2D-NMR (HMQC & HMBC) besides the comparison of the data with the literature. The extracts and phytoconstituents were evaluated in vitro for their activity against some bacterial pathogens, which represent prominent human pathogens, particularly in hospital settings. The antibacterial activity was examined against three Gram-positive bacterial strains (Staphylococcus aureus, Staphylococcus epidermidis & Enterococcus faecalis) and five Gram-negative ones (Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella pneumoniae, Proteus mirabilis & Salmonella typhimurium) relative to Ciprofloxacin as a reference drug. Furthermore, the in vitro antidiabetic activity (Type II) was evaluated using the alpha-glucosidase inhibitory assay.
RESULTS:
Five flavone C-glycosides namely; Apigenin 8-C-β-D-glucopyranoside (vitexin) (1), 2''-Oxylopyranosylvitexin (2), acacetin 8-C-β-D-glucopyranoside (3), acacetin 8-C-α-L-rhamnoside (4), and 6,8-di-C-β-D-glucopyranosylapigenin (vecinin-II) (5) were isolated from n-butanol extract of B. vulgaris subspecies cicla L. var. flavescens. Compound 1 showed a promising antibacterial activity against most of the test bacterial strains with respect to the minimum inhibitory concentration values (MIC) ranged from 1.95 to 15.63 µg ml-1. On the other hand, compounds 1 and 3 demonstrated superior antidiabetic activities with IC50 values of 35.7 and 42.64 µg ml-1, respectively, while an inferior potential antidiabetic activity was recorded for compound 4 (IC50 = 145.5 µg ml-1) in comparison with Acarbose as a reference drug.
CONCLUSION:
B. vulgaris L. is an edible plant, which could be used as a natural source of antibiotic and hypoglycemic drugs.

Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

KEYWORDS:
Amaranthaceae; Beta vulgaris subspecies cicla L. var. flavescens; antibacterial; antidiabetic; flavonoids; saponins.

DOI:

10.2174/1389201020666190613161212

(2)

Arch Virol. 2019 Sep;164(9):2265-2275. doi: 10.1007/s00705-019-04305-x. Epub 2019 Jun 14.

Elimination of multidrug-resistant Proteus mirabilis biofilms using bacteriophages.

Gomaa S¹, Serry F², Abdellatif H², Abbas H².

Author information

Abstract

Proteus mirabilis is responsible for a wide range of infections that affect the urinary tract, the respiratory tract, burns, wounds and the feet of individuals with diabetes. They are highly resistant to antimicrobial agents, and new therapeutic options are therefore needed to combat this pathogen. The use of bacteriophages is one option that may be useful in treating multidrug-resistant (MDR) Proteus mirabilis infections, especially biofilm-based infections. The aim of this study was to control biofilms formed by MDR Proteus mirabilis using bacteriophages. Proteus mirabilis isolates were identified based on biochemical tests, and their resistance profiles were determined by the disk diffusion method. The biofilm-forming capacity of the isolates was assessed by the spectrophotometric method. Bacteriophages attacking Proteus mirabilis were isolated from sewage. The effect of phage on biofilm formation was investigated by the viable count method. A high rate of drug resistance was found (87.2%). Strong biofilm formation was observed in 80.5% of isolates, while moderate production was found in 19.5%. Five bacteriophages were isolated from sewage and were tested for their ability to eliminate biofilms. Significant disruption of pre-formed biofilms was observed that reached up to 99.9% decrease in the number of viable cells. The use of bacteriophages is considered a promising strategy against the biofilm infections caused by MDR Proteus mirabilis isolates.

PMID:

31197549

DOI:

10.1007/s00705-019-04305-x

[Indexed for MEDLINE]

Serralysin 2020, ( ilman kommenttiani)

https://id.nlm.nih.gov/mesh/C095666.html

About:

serralysin http://id.nlm.nih.gov/mesh/C095666

Type:

MeSH SCR ChemicalThese are chemicals, drugs, enzymes, vitamins, etc.
more types...

Related to

preferredConcept (MeSH Concept)

• serralysin

preferredMappedTo (MeSH TopicalDescriptor)

• Metalloendopeptidases

preferredTerm (MeSH Term)

• T281894

frequency

• "47"

active

• "true"

dateCreated

• "1995-10-17"

dateRevised

• "2004-08-06"

identifier

• "C095666"

note

• "zinc metalloproteinases with broad similar specificity for cleavage of the oxidized insulin B chain"

source

• "Methods Enzymol 1995;248:395-413"

label

• "serralysin"

https://febs.onlinelibrary.wiley.com/doi/full/10.1111/j.1742-4658.2007.05739.x

Serralysiiniperhe (ihmisvihollisia), Virulenssiproteiinisetti

https://www.researchgate.net/figure/Phylogenetic-linkage-of-ZapA-to-the-serralysin-family-of-zinc-metalloproteases-Analysis_fig2_15607465
 

Phylogenetic linkage of ZapA to the serralysin family of zinc metalloproteases. Analysis of the deduced amino acid sequence of ZapA indicates the presence of several signature peptide motifs that are held in common with many other homologous metalloproteases belonging to the serralysin family of metalloproteases, including the proteases of S. marcescens, E. chrysanthemi, P. aeruginosa, and (from this research) P. mirabilis. 

The serralysin family has the zinc metalloprotease domain, the Met turn of metzincins, and three or more Ca 2 binding motifs, and all are exported by a COOH terminal secretory signal. The serralysin family of zinc metalloproteases is in turn part of a larger set of proteins thought to function as virulence factors in several genera of bacteria. 

This set of virulence proteins includes

 Actinobacillus (Haemophilus) pleuropneumoniae hemolysin protein, AppA (18), 

Actinobacillus suis AppA (17), 

Pasteurella haemolytica LktA leukotoxin (20),

 enterohemorrhagic E. coli HlyA hemolysin (33), 

Actinobacillus actinomycetemcomitans LktA leukotoxin (40, 41),

 Bordetella pertussis adenylate cyclase CyaA (16), 

N. meningitidis Fe-regulated RTX cytotoxin homolog (FrpA) (64),

 and Pseudomonas fluorescens lipase LipA (27, 63).

 All of these proteins have the common feature of the Ca 2 binding GGXGXD repeat motif among other characteristics. 

The phylogenetic linkage map was established from nucleotide and amino acid sequences stored in the GenBank, EMBL, and Pir libraries and was analyzed with the Genetics Computer Group program PILEUP.

....
 . One of these factors, ZapA metalloprotease, is of distinctive significance. It is an IgA-degrading protease that is specifically expressed during differentiation of swimmer into swarmer cells ( Wassif et al., 1995). Now-a-days due to increasing antibiotic resistance in Enterobacteriaceae, the multidrug resistant (MDR) strains of Proteus species have also been reported worldwide. ...

Serralysiinin kaltaisten  metalloproteaasien C-terminaalin piirteitä: 

https://www.ebi.ac.uk/interpro/entry/InterPro/IPR011049/

serralysin MeSH Supplementary Concept Data 2020

• Details
• Concepts

MeSH Supplementary

serralysin

Unique ID

C095666

RDF Unique Identifier

http://id.nlm.nih.gov/mesh/C095666

Registry Number

EC 3.4.24.40

Heading Mapped to

*Metalloendopeptidases

Frequency

47

Note

zinc metalloproteinases with broad similar specificity for cleavage of the oxidized insulin B chain

Source

Methods Enzymol 1995;248:395-413

Date of Entry

1995/10/17

Revision Date

2004/08/06

 

Metzinkiiniperheen ( klaani MA) tietoa 2009: metioniinia sisältävä Met-turn ja pitkä sinkkiä sitova konsensusmotiivi

J Biol Chem. 2009 Jun 5;284(23):15353-7. doi: 10.1074/jbc.R800069200. Epub 2009 Feb 5.Catalytic domain architecture of metzincin metalloproteases.

Gomis-Rüth FX¹. Abstract

Metalloproteases cleave proteins and peptides, and deregulation of their function leads to pathology. An understanding of their structure and mechanisms of action is necessary to the development of strategies for their regulation. Among metallopeptidases are the metzincins, which are mostly multidomain proteins with approximately 130-260-residue globular catalytic domains showing a common core architecture characterized by a long zinc-binding consensus motif, HEXXHXXGXX(H/D), and a methionine-containing Met-turn.
 Metzincins participate in unspecific protein degradation such as digestion of intake proteins and tissue development, maintenance, and remodeling, but they are also involved in highly specific cleavage events to activate or inactivate themselves or other (pro)enzymes and bioactive peptides. Metzincins are subdivided into families, and seven such families have been analyzed at the structural level:
the astacins,
ADAMs/adamalysins/reprolysins,
serralysins,
 matrix metalloproteinases,
 snapalysins,
leishmanolysins, and
 pappalysins.
These families are reviewed from a structural point of view.

DOI:

10.1074/jbc.R800069200

[Indexed for MEDLINE]

2020 katson uusinta tietoa serralysiineistä.

 

2013   tietoa

Serralysin and Related Enzymes

Ulrich Baumann, in Handbook of Proteolytic Enzymes (Third Edition), 2013

Name and History

Serralysin was first discovered in the culture medium of Serratia sp. E-15 [1] and was named from the genus name Serratia+lysin. Similar proteases have been found to be secreted by other Gram-negative bacteria, e.g. Pseudomonas aeruginosa [2] and Erwinia chrysanthemi [3–6], Ps. fluorescens [7,8], or Photorhabdus luminescens [9]. These proteases are quite similar in their physicochemical properties and are grouped together in the serralysin subfamily. Later, it was established on evidence from three-dimensional structures that serralysins, together with matrix metalloproteases, astacins and snake venom proteinases, belong to clan MA (the metzincins) [10].

Serralysiiniperhe Metzinkiinisuperperheessä. Esimerkki. vuodelta 1999.

Biosci Biotechnol Biochem. 1999 Jul;63(7):1165-70.

Identification of a member of the serralysin family isolated from a psychrotrophic bacterium, Pseudomonas fluorescens 114.

Kumeta H¹, Hoshino T, Goda T, Okayama T, Shimada T, Ohgiya S, Matsuyama H, Ishizaki KAbstract

An extracellular metalloprotease named No. 114 protease is one of the major secretions of a psychrotrophic bacterium, Pseudomonas fluorescens 114, the cold-adaptation mechanism of which has not been identified. In this study, we purified and cloned No. 114 protease, which is a single polypeptide having a molecular mass of 47 kDa. This protease contains a zinc-binding motif (HEXXHXUGUXH: X, arbitrary amino acid; U, bulky hydrophobic amino acid), glycine-rich repeats (GGXGXD) and no cysteine residue, which are the features specifically found in serralysin subfamily. No. 114 protease has its maximum activity at the temperature of 35-40 degrees C, which is about 20 degrees C lower than that of a serralysin from a mesophilic bacterium, Pseudomonas aeruginosa. All these results imply that No. 114 protease from this psychrophilic bacterium is a unique member of the serralysin group characterized by a low optimal temperature.

PMID:

10478443

DOI:

10.1271/bbb.63.1165

[Indexed for MEDLINE]

Free full text

METZINCIN- superfamily -kartta.

https://www.researchgate.net/figure/The-metzincin-gene-family-A-Schematic-representation-of-subdivisions-within-the_fig1_6388280

Tässä Met viitaa methionine- aminohappoon, joka  propeptidissä merkitsee  Met turn- kohdan muodostumista  tiukka  silmukkaan  (" tigh hair pin loop", jossa  propeptidin alueella sijaitseva C ja aktiivin kohdan alueen  3 histidiinin (H) kesken  koordinoituu Zn++ siten, että aktiivi kohta esittytyy. 
 

4-siipinen propelli on hemopexiinin kaltaisten proteiinien superperheessä , kuten usealla MMP- proteiinilla

MMP1 (11q22.2) sinkistä riippuva MMP, ZnMc matrilysiini domeenin ja HX propellin omaava. Hemopexiinitoistoa 4-siipi propellina

1. ORIGIN 1 mqeffglkvt gkpdaetlkv MkqPRCGVPD vaqfvltegn prweqthlty rienytpdlp
   

          61 radvdhaiek afqlwsnvtp ltftkvsegq adimisfvrg dhrdnspfdg pggnlahafq
         121 pgpgiggdah fdederwtnn freynlhrva aHElgHslgl sHstdigalm ypsytfsgdv
         181 qlaqddidgi qaiygrsqnp vqpigpqtpk acdskltfda ittirgevmf fkdrfymrtn
         241 pfypevelnf isvfwpqlpn gleaayefad rdevrffkgn kywavqgqnv lhgypkdiys
         301 sfgfprtvkh idaalseent gktyffvank ywrydeykrs mdpgypkmia hdfpgighkv
         361 davfmkdgff yffhgtrqyk fdpktkrilt lqkanswfnc rkn
   //

    (Tästä mtixmetalloproteiinista on useita  artikkeleita PubMed lähteestä vuodelta 2019. Nyt katson nitä MMP- molekyylejäuudestaan. ne ovat sinkistä riippuvaisia. Katalyyttisessä kohdassa on  Zn ja Hemopexiinipropelli koordinoi  Zn tai Calsiumia.
   Signaalipeptidin jälkeen  oleva propeptidio on n 80 aminoappoa ja siinä on tunnusomaista konservatiivinen sekvenssi PRCG(C/N)PD, tässä  peptidissä se on 24..30  kohdalla. Siinä näkyvä cysteiini(C)  kiinnitty katalyyttisen domeenin Zn metalliin ja pitää täten yllä  MMP-proteiinin latenssitilaa , propeptidimuotoa (pro-MMP). 
   Katalyyttinen kohta on 42..195, " ZnMc_MMP.  Siinä on sinkkiä sitova kohta jakson keskellä motiivissa HEXXHXUGUXH, (U tarkoittaa hydrofobista bulk-aminohappoa) .  
   H152, E153, H156, H162.  
   C-terminaalissa päin oleva hemopexiini moduli (HX toistoja 4) , 4-siipinen propelli, jota sitoutuneet metallit pitävät koossa  2-siipinen  propelli,   sinkkia tai  kalsiumia metallina.  
    (Hemopexin-like superfamily- tunnus)
   NM_001145938.2 → NP_001139410.1  interstitial collagenase isoform 2
   See identical proteins and their annotated locations for NP_001139410.1
   
   Status: REVIEWED

   Description

   Transcript Variant: This variant (2) uses an alternate in-frame splice site in the 5' coding region and uses a downstream start codon compared to variant 1. The resulting protein (isoform 2) has a shorter N-terminus compared to isoform 1.

   Source sequence(s)

   AK297723, AP000619

   UniProtKB/TrEMBL

   B4DN15

   Conserved Domains (4) summary

   cd00094
   Location:209 → 400

   HX; Hemopexin-like repeats.; Hemopexin is a heme-binding protein that transports heme to the liver. Hemopexin-like repeats occur in vitronectin and some matrix metalloproteinases family (matrixins). The HX repeats of some matrixins bind tissue inhibitor of  metalloproteinases (TIMPs). This CD contains 4 instances of the repeat.

    

   cd04278
   Location:42 → 195

   weqthlty rienytpdlp
          61 radvdhaiek afqlwsnvtp ltftkvsegq adimisfvrg dhrdnspfdg pggnlahafq
         121 pgpgiggdah fdederwtnn freynlhrva ahelghslgl shstdigalm ypsytfsgdv
         181 qlaqddidgi qaiyg

   ZnMc_MMP; Zinc-dependent metalloprotease, matrix metalloproteinase (MMP) sub-family. MMPs are responsible for a great deal of pericellular proteolysis of extracellular matrix and cell surface molecules, playing crucial roles in morphogenesis, cell fate ..specification, cell migration, tissue repair, tumorigenesis, gain or loss of tissue-specific functions, and apoptosis. In many instances, they are anchored to cell membranes via trans-membrane domains, and their activity is controlled via TIMPs (tissue inhibitors of metalloproteinases).

   Feature 1:active site [active site]

   Evidence:

   • Comment:consensus motif: HEXXHXUGUXH U= bulky hydrophobic
   • Comment:coordinates zinc, contains catalytic Glu
   • Citation:PMID 8253063
   • Structure:1BQQ: Human type-1 matrix metalloprotease coordinates zinc
     - View structure with Cn3D
   • Citation:PMID 9724659

    

    

   pfam00413

    
   Location:42 → 195

   Peptidase_M10; MatrixinThe members of this family are enzymes that cleave peptides. These proteases require zinc for catalysis.

   pfam01471
   Location:1 → 21

   PG_binding_1; Putative peptidoglycan binding domainThis domain is composed of three alpha helices. This domain is found at the N or C terminus of a variety of enzymes involved in bacterial cell wall degradation. .. This domain may have a general peptidoglycan binding function. This family is found N-terminal to the catalytic domain of matrixins. The domain is found to bind peptidoglycan experimentally.

    
   

Matrixmetalloproteinaasit omaavat sinkkiä sitovan kohdan, jota inhibiittori käyttää hyödyksi.

https://www.ncbi.nlm.nih.gov/pubmed/15723627

Curr Pharm Des. 2005;11(3):295-322.

Recent developments in the design of specific Matrix Metalloproteinase inhibitors aided by structural and computational studies.

Rao BG¹.

Abstract

It has been 10 years since a 3-dimensional structure of the catalytic domain of a Matrix Metalloprotease (MMP) was revealed for the first time in 1994. More than 80 structures of different MMPs in apo and inhibited forms, determined by X-ray crystallography and NMR methods, have been published by the end of year 2003. A large number of very potent inhibitors have been disclosed in published and patent literature. Several MMP inhibitors entered clinical trials for the treatment of cancer and arthritis. Most of the first generation inhibitors have hydroxamic acid as the Zinc-binding group and have limited specificity. With the failure of these inhibitors in clinical trials, more efforts have been directed to the design of specific inhibitors with different Zn-binding groups in recent years. This review will summarize all the published structural information and focus on the inhibitors that were designed to take advantage of the nonprime side of the MMP active site using structural information and computational analysis. Representative structures from all MMPs are aligned to a target structure to provide a better understanding of the similarities and differences of the active site pockets. This analysis supports the view that the differences in the nonprime side pockets provide better opportunities for designing inhibitors with higher specificity. Published information on all the Zinc-binding groups of MMP inhibitors is reviewed for the first time. Pros and cons of inhibitors with non-hydroxamate Zinc-binding groups in terms of specificity, toxicity and pharmacokinetic properties are discussed.

PMID:

15723627

DOI:

10.2174/1381612053382115

[Indexed for MEDLINE]