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Literature summary for 3.4.24.86 extracted from

  • Minond, D.; Cudic, M.; Bionda, N.; Giulianotti, M.; Maida, L.; Houghten, R.; Fields, G.
    Discovery of novel inhibitors of a disintegrin and metalloprotease 17 (ADAM17) using glycosylated and non-glycosylated substrates (2012), J. Biol. Chem., 287, 36473-36487.
    View publication on PubMedView publication on EuropePMC

Activating Compound

Activating Compound Comment Organism Structure
additional information substrate glycosylation increases the enzyme activity, overview Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(5S)-4-(cyclopentylmethyl)-5-(4-hydroxybenzyl)-1-[(2S)-1-(2-[[(6S)-6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]piperazine-2,3-dione 90% inhibition at 0.04 mM Homo sapiens
(5S)-5-(4-hydroxybenzyl)-1-[(2S)-1-(2-[[(6S)-6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]-4-[2-(tricyclo[3.3.1.13,7]dec-1-yl)ethyl]piperazine-2,3-dione 95% inhibition at 0.04 mM Homo sapiens
1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)-4-[3-adamantylpropyl]piperazine-2,3-dione
-
Homo sapiens
1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(naphthalen-2-yl)propan-2-yl]-5-(4-hydroxybenzyl)-4-[3-adamantylpropyl]piperazine-2,3-dione
-
Homo sapiens
4-(2-butylbenzyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
-
Homo sapiens
4-(2-butylbenzyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(naphthalen-2-yl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
-
Homo sapiens
4-(2-butylbenzyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]piperazine-2,3-dione
-
Homo sapiens
4-(2-butylbenzyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]piperazine-2,3-dione design and synthesis of the specific inhibitor, overview Homo sapiens
4-(cyclopentylmethyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
-
Homo sapiens
4-(cyclopentylmethyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(naphthalen-2-yl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
-
Homo sapiens
4-(cyclopentylmethyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]piperazine-2,3-dione
-
Homo sapiens
4-(cyclopentylmethyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]piperazine-2,3-dione design and synthesis of the specific inhibitor, overview Homo sapiens
5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]-4-[3-adamantylpropyl]piperazine-2,3-dione
-
Homo sapiens
5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]-4-[3-adamanylpropyl]piperazine-2,3-dione
-
Homo sapiens
5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]-4-[3-adamantylpropyl]piperazine-2,3-dione
-
Homo sapiens
additional information secondary binding site (exosite) inhibitors provide a viable alternative to active site inhibitors, library screening and inhibitor design and synthesis, ADAM17 inhibition occurs via a non-zinc-binding mechanism, kinetic study, overview Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
0.003
-
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser(4O-(beta-D-Gal-(1->3)-alpha-D-GalNAc))-Ser-Lys(DABCYL) pH 7.5, 22°C Homo sapiens
0.012
-
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Lys(DABCYL) pH 7.5, 22°C Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Zn2+ active site zinc, metalloprotease Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
additional information Homo sapiens analysis of ADAM cognate substrates reveals that glycosylation is often present in the vicinity of the scissile bond ?
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens P78536
-
-

Source Tissue

Source Tissue Comment Organism Textmining
commercial preparation
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser(4O-(beta-D-Gal-(1->3)-alpha-D-GalNAc))-Ser-Lys(DABCYL) + H2O
-
Homo sapiens Glu(EDANS)-Pro-Leu-Ala-Gln-Ala + Val-Arg-Ser-Ser(4O-(beta-D-Gal-(1->3)-alpha-D-GalNAc))-Ser-Lys(DABCYL)
-
?
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Lys(DABCYL) + H2O
-
Homo sapiens Glu(EDANS)-Pro-Leu-Ala-Gln-Ala + Val-Arg-Ser-Ser-Ser-Lys(DABCYL)
-
?
interleukin-6 receptor + H2O the cleavage site by ADAM17 is LPVQ357-/-DSSV, N-linked glycosylation sites are: Asn55, Asn93, Asn221, Asn350 Homo sapiens ?
-
?
additional information analysis of ADAM cognate substrates reveals that glycosylation is often present in the vicinity of the scissile bond Homo sapiens ?
-
?
additional information high throughput screening assays are developed using glycosylated and non-glycosylated substrate, and positional scanning, substrate specificity, overview Homo sapiens ?
-
?
Pro-BTC + H2O the cleavage site by ADAM17 is CVVA31-/-DGNS, N-linked glycosylation site is Asn34 Homo sapiens ?
-
?
pro-EPR + H2O the cleavage site by ADAM17 is DNPR59-/-VAQV, N-linked glycosylation site is Asn47 Homo sapiens ?
-
?
pro-HB-EGF + H2O the cleavage site by ADAM17 is RKVR62-/-DLQE, O-linked glycosylation sites are Thr75 and Thr85 Homo sapiens ?
-
?
pro-TGFalpha + H2O the cleavage site by ADAM17 is VAAA39-/-VVSH, N-linked glycosylation site is Asn25 Homo sapiens ?
-
?
pro-tumor necrosis factor alpha + H2O with and without a glycan moiety attached, glycosylation increases the enzyme activity. The cleavage site of TNFalpha by ADAM17 is only four residues away from a glycosylated residues, whereas glycosylation occurs 14 residues away from the TGFalpha cleavage site. Cleavage site for ADAM-17 is LAQA76-/-VRSS, O-linked glycosylation site is Ser80 Homo sapiens ?
-
?
proheparin-binding EGF-like growth factor + H2O
-
Homo sapiens ? cleavage occurs between residues RKVR62-DLQE. Substrate shows O-linked glycosylation 13 residues apart from scissile bond ?
proTNF-alpha + H2O
-
Homo sapiens soluble TNF-alpha cleavage occurs between residues LAQA76-VRSS. Substrate shows O-linked glycosylation 4 residues apart from scissile bond ?
protransforming growth factor alpha + H2O
-
Homo sapiens ? cleavage occurs between residues AAA39-VVSH. Substrate shows N-linked glycosylation 14 residues apart from scissile bond ?
transferrin receptor protein 1 + H2O
-
Homo sapiens ? cleavage occurs between residues ECER100-LAGT. Substrate shows O-linked glycosylation 4 residues apart from scissile bond ?
TRP1 + H2O the cleavage site by ADAM17 is ECER100-/-LAGT, O-linked glycosylation sites are: Thr104, Asn251, Asn317, Asn727 Homo sapiens ?
-
?

Synonyms

Synonyms Comment Organism
a disintegrin and metalloprotease 17
-
Homo sapiens
ADAM-17
-
Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
22
-
assay at room temperature Homo sapiens

Turnover Number [1/s]

Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
0.14
-
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Lys(DABCYL) pH 7.5, 22°C Homo sapiens
0.25
-
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser(4O-(beta-D-Gal-(1->3)-alpha-D-GalNAc))-Ser-Lys(DABCYL) pH 7.5, 22°C Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.5
-
assay at Homo sapiens

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
additional information
-
additional information inhibition kinetics, overview Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.017
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.018
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.031
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.032
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.034
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]piperazine-2,3-dione
0.035
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]piperazine-2,3-dione
0.038
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]piperazine-2,3-dione
0.039
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.04
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.042
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]piperazine-2,3-dione
0.045
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.05
-
pH 7.5, 22°C Homo sapiens 1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)-4-[3-adamantylpropyl]piperazine-2,3-dione
0.05
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]piperazine-2,3-dione
0.051
-
pH 7.5, 22°C Homo sapiens 1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(naphthalen-2-yl)propan-2-yl]-5-(4-hydroxybenzyl)-4-[3-adamantylpropyl]piperazine-2,3-dione
0.051
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(naphthalen-2-yl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.053
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]piperazine-2,3-dione
0.054
-
pH 7.5, 22°C Homo sapiens 1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)-4-[3-adamantylpropyl]piperazine-2,3-dione
0.054
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(naphthalen-2-yl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.054
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]piperazine-2,3-dione
0.056
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(naphthalen-2-yl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.056
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(naphthalen-2-yl)propan-2-yl]-5-(4-hydroxybenzyl)piperazine-2,3-dione
0.056
-
pH 7.5, 22°C Homo sapiens 5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]-4-[3-adamantylpropyl]piperazine-2,3-dione
0.057
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]piperazine-2,3-dione
0.058
-
pH 7.5, 22°C Homo sapiens 1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(naphthalen-2-yl)propan-2-yl]-5-(4-hydroxybenzyl)-4-[3-adamantylpropyl]piperazine-2,3-dione
0.058
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]piperazine-2,3-dione
0.059
-
pH 7.5, 22°C Homo sapiens 1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)-4-[3-adamantylpropyl]piperazine-2,3-dione
0.059
-
pH 7.5, 22°C Homo sapiens 4-(2-butylbenzyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]piperazine-2,3-dione
0.06
-
pH 7.5, 22°C Homo sapiens 1-[1-[2-[(2,3-dioxo-6-propylpiperazin-1-yl)methyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)propan-2-yl]-5-(4-hydroxybenzyl)-4-[3-adamantylpropyl]piperazine-2,3-dione
0.06
-
pH 7.5, 22°C Homo sapiens 5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]-4-[3-adamantylpropyl]piperazine-2,3-dione
0.061
-
pH 7.5, 22°C Homo sapiens 5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]-4-[3-adamantylpropyl]piperazine-2,3-dione
0.062
-
pH 7.5, 22°C Homo sapiens 5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(4-hydroxyphenyl)propan-2-yl]-4-[3-adamanylpropyl]piperazine-2,3-dione
0.066
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]piperazine-2,3-dione
0.09
-
pH 7.5, 22°C Homo sapiens 4-(cyclopentylmethyl)-5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]piperazine-2,3-dione
0.095
-
pH 7.5, 22°C Homo sapiens 5-(4-hydroxybenzyl)-1-[1-(2-[[6-(4-hydroxybenzyl)-2,3-dioxopiperazin-1-yl]methyl]pyrrolidin-1-yl)-3-(naphthalen-2-yl)propan-2-yl]-4-[3-adamantylpropyl]piperazine-2,3-dione

kcat/KM [mM/s]

kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
12
-
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Lys(DABCYL) pH 7.5, 22°C Homo sapiens
76
-
Glu(EDANS)-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser(4O-(beta-D-Gal-(1->3)-alpha-D-GalNAc))-Ser-Lys(DABCYL) pH 7.5, 22°C Homo sapiens