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Literature summary for 3.4.23.B24 extracted from
- Differential inhibition of signal peptide peptidase family members by established gamma-secretase inhibitors (2015), PLoS ONE, 10, e0128619 .
Application
| Application | Comment | Organism |
|---|---|---|
| medicine | the signal peptide peptidase hSPP is a biomedically important protease implicated as therapeutic target for hepatitis C | Homo sapiens |
| medicine | the signal peptide peptidase pSPP is a biomedically important protease implicated as therapeutic target for treatement of Plasmodia and malaria | Plasmodium sp. |
| medicine | the signal peptide peptidase SPPL2a is a biomedically important protease implicated as therapeutic target for B-cell immunomodulation and neoplasia | Mus musculus |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| recombinant expression of FLAG-tagged enzyme in HEK-293T cells, coexpression with FLAG-tagged substrate FBA | Mus musculus |
| recombinant expression of FLAG-tagged enzyme in HEK-293T cells, coexpression with FLAG-tagged substrate FBA | Homo sapiens |
| recombinant expression of FLAG-tagged enzyme in HEK-293T cells, coexpression with FLAG-tagged substrate FBA | Plasmodium sp. |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide | i.e. Compound E | Homo sapiens |  |
| (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide | i.e. Compound E, below 50% inhibition | Mus musculus | |
| 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] | i.e. (Z-LL)2 ketone, causes over 75% inhibition of FBA cleavage at 0.01 mM | Homo sapiens | |
| 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] | i.e. (Z-LL)2 ketone, causes over 75% inhibition of FBA cleavage at 0.01 mM | Mus musculus | |
| 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] | i.e. (Z-LL)2 ketone, causes over 75% inhibition of FBA cleavage at 0.01 mM | Plasmodium sp. | |
| GSI II | a gamma-secretase inhibitor | Homo sapiens | |
| GSI II | a gamma-secretase inhibitor | Mus musculus | |
| GSI II | a gamma-secretase inhibitor | Plasmodium sp. | |
| L685,458 | - |
Homo sapiens | |
| L685,458 | - |
Mus musculus | |
| L685,458 | - |
Plasmodium sp. | |
| LY-411,575 | - |
Homo sapiens | |
| LY-411,575 | - |
Mus musculus | |
| LY-411,575 | - |
Plasmodium sp. | |
| additional information | no inhibition by N-[(1S)-2-[[(7S)-6,7-Dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ); no inhibition by (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E) and N-[(1S)-2-[[(7S)-6,7-Dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ) | Mus musculus | |
| additional information | no inhibition by (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E) and N-[(1S)-2-[[(7S)-6,7-Dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ) | Plasmodium sp. | |
| N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide | i.e. DBZ | Homo sapiens | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| CD74 + H2O | Mus musculus | although SPPL2b can cleave CD74 when overexpressed, it does not appear contribute to CD74 NH2-terminal fragment turnover | ? | - |
? | |
| CD74 + H2O | Mus musculus | SPPL2a cleaves CD74 and contributes to CD74 NH2-terminal fragment turnover | ? | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | - |
- |
- |
| Mus musculus | - |
- |
- |
| Plasmodium sp. | - |
- |
- |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| B-lymphocyte | - |
Mus musculus | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| CD74 + H2O | - |
Mus musculus | ? | - |
? | |
| CD74 + H2O | although SPPL2b can cleave CD74 when overexpressed, it does not appear contribute to CD74 NH2-terminal fragment turnover | Mus musculus | ? | - |
? | |
| CD74 + H2O | SPPL2a cleaves CD74 and contributes to CD74 NH2-terminal fragment turnover | Mus musculus | ? | - |
? | |
| Fba + H2O | a recombinant substrate consisting of the amino-terminus of BRI2 fused to amyloid beta 1-25, with a K16A mutation incorporated to prevent potential alpha-secretase cleavage that would preclude ELISA based detection of the released COOH-terminal fragment. The enzyme shows different cleavage site specificity compared to other signal peptide peptidases, the cleavage may be processive | Mus musculus | ? | - |
? | |
| Fba + H2O | a recombinant substrate consisting of the amino-terminus of BRI2 fused to amyloid beta 1-25, with a K16A mutation incorporated to prevent potential alpha-secretase cleavage that would preclude ELISA based detection of the released COOH-terminal fragment. The enzyme shows different cleavage site specificity compared to other signal peptide peptidases, the cleavage may be processive. hSPP processes of FBA resulting in a gap between the carboxyl end of the ICD and the NH2-terminus of the CTF | Homo sapiens | ? | - |
? | |
| Fba + H2O | a recombinant substrate consisting of the amino-terminus of BRI2 fused to amyloid beta 1-25, with a K16A mutation incorporated to prevent potential alpha-secretase cleavage that would preclude ELISA based detection of the released COOH-terminal fragment. The enzyme shows different cleavage site specificity compared to other signal peptide peptidases, the cleavage may be processive. hSPP processes of FBA resulting in a gap between the carboxyl end of the ICD and the NH2-terminus of the CTF. Enzyme pSPP may have more than one cleavage site | Plasmodium sp. | ? | - |
? | |
| Fba + H2O | a recombinant substrate consisting of the amino-terminus of BRI2 fused to amyloid beta 1-25, with a K16A mutation incorporated to prevent potential alpha-secretase cleavage that would preclude ELISA based detection of the released COOH-terminal fragment. The enzyme shows different cleavage site specificity compared to other signal peptide peptidases, the cleavage may be processive. hSPP processes of FBA resulting in a gap between the carboxyl end of the ICD and the NH2-terminus of the CTF. SPPL2b reduced levels of the intact FBA substrate by over 90%, which is higher than the activity of other SPPs | Mus musculus | ? | - |
? | |
| additional information | cleavage occurs following ectodomain shedding by signal peptidase (SP) for hSPP | Mus musculus | ? | - |
- |
|
| additional information | cleavage occurs following ectodomain shedding by signal peptidase (SP) for hSPP | Mus musculus | ? | - |
? | |
| additional information | cleavage occurs following ectodomain shedding by signal peptidase (SP) for hSPP | Homo sapiens | ? | - |
- |
|
| additional information | cleavage occurs following ectodomain shedding by signal peptidase (SP) for hSPP | Homo sapiens | ? | - |
? | |
| TfR 1 + H2O | intramembrane cleavage sites | Mus musculus | ? | - |
? | |
| TNF-alpha + H2O | intramembrane cleavage sites | Mus musculus | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| ? | x * 48000, about, sequence calculation | Homo sapiens |
| ? | x * 63000, about, sequence calculation | Mus musculus |
| ? | x * 37000, recombinant FLAG-tagged enzyme, SDS-PAGE, x * 52000, about, sequence calculation | Plasmodium sp. |
| ? | x * 69000, about, sequence calculation | Mus musculus |
| More | the monomeric form is the dominant species observed for the recombinant enzyme, with lesser amounts of dimer and trimer | Mus musculus |
| More | the monomeric form is the dominant species observed for the recombinant enzyme, with lesser amounts of dimer and trimer | Homo sapiens |
| More | the monomeric form is the dominant species observed for the recombinant enzyme, with lesser amounts of dimer and trimer. The enzyme has multiple intracellular domains (ICDs) | Plasmodium sp. |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| hSPP | - |
Homo sapiens |
| hSPP | - |
Plasmodium sp. |
| signal peptide peptidase like 2a | - |
Mus musculus |
| SPP | - |
Homo sapiens |
| SPP | - |
Plasmodium sp. |
| SPPL | - |
Mus musculus |
| SPPL2a | - |
Mus musculus |
| SPPL2b | - |
Mus musculus |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.000051 | - |
pH and temperature not specified in the publication | Mus musculus | LY-411,575 | |
| 0.00015 | - |
pH and temperature not specified in the publication | Homo sapiens | LY-411,575 | |
| 0.000161 | - |
pH and temperature not specified in the publication | Plasmodium sp. | L685,458 | |
| 0.000177 | - |
pH and temperature not specified in the publication | Mus musculus | 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] | |
| 0.000319 | - |
pH and temperature not specified in the publication | Homo sapiens | L685,458 | |
| 0.000423 | - |
pH and temperature not specified in the publication | Homo sapiens | GSI II | |
| 0.000427 | - |
pH and temperature not specified in the publication | Plasmodium sp. | GSI II | |
| 0.000472 | - |
pH and temperature not specified in the publication | Plasmodium sp. | 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] | |
| 0.000519 | - |
pH and temperature not specified in the publication | Homo sapiens | 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] | |
| 0.00057 | - |
pH and temperature not specified in the publication | Mus musculus | L685,458 | |
| 0.000876 | - |
pH and temperature not specified in the publication | Mus musculus | L685,458 | |
| 0.000948 | - |
pH and temperature not specified in the publication | Homo sapiens | N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide | |
| 0.00146 | - |
pH and temperature not specified in the publication | Homo sapiens | (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide | |
| 0.00214 | - |
pH and temperature not specified in the publication | Mus musculus | 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] | |
| 0.00348 | - |
pH and temperature not specified in the publication | Plasmodium sp. | LY-411,575 | |
| 0.0036 | - |
pH and temperature not specified in the publication | Mus musculus | GSI II | |
| 0.0055 | - |
pH and temperature not specified in the publication | Mus musculus | LY-411,575 | |
| 0.0088 | - |
pH and temperature not specified in the publication | Mus musculus | GSI II | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase | Mus musculus |
| evolution | similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase | Homo sapiens |
| evolution | similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase | Plasmodium sp. |
| malfunction | depletion of SPPL2a leads to accumulation of an NH2-terminal fragment (NTF) of CD74 which impairs B cell development and survival | Mus musculus |
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