Naturally-Occurring Tyrosinase Inhibitors Classified by Enzyme Kinetics and Copper Chelation
and Cheorl-Ho Kim 1,*
Round 1
Reviewer 1 Report
Dear Authors, please carefully check the content for writing style, chemical names, chemical structures, abbreviations, and English. Few examples given below:
1- The chemical structures and chemical names should be revised and corrected.
2- A table with the activity value(s) for each of every compound listed needs to be constructed.
3- Discussion of the activity within the standard activity margins needs to be discussed.
4- Classification of the inhibitors according to the chemical class and SARS will be helpful/interesting to the reader.
5- The authors need to be careful and match between different names of the same molecule (lines 129/135; vitamin C = L-ascorbic acid), and correctly discuss the same, also in line 134, arbutin was mentioned twice.
6- The paragraph, between lines 132-137, needs careful re-phrasing.
7- Line 150, please correct and re-phrase.
8- Line 154, check the typos.
9- please write L-DOPA correctly.
10- line 156, please correct the chemical name, and many more in the text.
Author Response
A) Review 1
1- The chemical structures and chemical names should be revised and corrected.
As suggested, the most compound structures are known. Chemical names are corrected with the additional Table 1-5.
2- A table with the activity value(s) for each of every compound listed needs to be constructed.
As suggested, the new Tables 1 to -5 have been constructed.
In line 370,
Table 1. Summarization of the competitive tyrosinase inhibitors
|
Compounds |
Property |
Competitive type |
Reference |
|
Hydroquinone |
α-/β-arbutins |
1,26 |
|
|
4-6-Hydroxy-2-naphthyl-1,3-bezendiol, resorcinol |
resorcin |
|
13 |
|
Anthocyanidin, aurone, flavan-3,4-diol |
flavonoid |
|
28 |
|
Kuwanon C, papyriflavonol A, sanggenon D, sophoflavescenol, flavonoid vinylation, lupinalbin, 7-O-gentibiosyl 2′-hydroxygenistein, gallocatechin, proanthocyanidins, (-)-8-Chlorocatechin, cyanidin, delphinidin, malvidin, pelargonidin, peonidin |
flavonoid derivative |
|
29,47,36, 52,53,56 |
|
3-O-β-Galactosyl quercetin, 3',5'-Di-C-β glucosyl phloretin, galactosyl-3-myricetin, potenserin C, 3-O-α-L-rhamnosyl quercetin-2-gallate |
flavonoid glycoside |
30 |
|
|
Apigenin, chrysin, luteolin, baicalein, mormin, cyclomorusin, morusin, norartocarpetin |
flavone |
|
31,37 |
|
Apigetrin, vitexin, baicalin, nobiletin, tangeretin, biflavone,7,8,4'-trihydroxy-isoflavone, 7,3',4'-trihydroxy-isoflavone, 3-O-β-D-glucosyl 4,5,5,7,7-pentahydroxy 3,3-dimethoxy 3,4-O-biflavone, isovitexin, baicalein, 6-hydroxyapigenin, 6-hydroxy-kaempferol, 6-hydroxygalangin, tricin (5,7,4-trihydroxy-3,5-dimethoxyflavone), vitexin |
flavone derivatives (C-glycosyl flavone, hydroxyflavone, flavone glucoside) |
monophenolase/ diphenolase |
32,33,34, 35,36,40,42 |
|
Quercetin, 4-O-b-D-glucosyl quercetin, β-D-glucosyl 3-O-6-O-malonyl quercetin, β-D-glucosyl 3-O-6-O-malonyl-kaempferol, morin, (±)2,3-cis-dihydromorin, 2,3-trans-dihydromorin, galangin, kaempferol, 8-prenylkaempferol, epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate, catechin, proanthocyanidin |
flavonol |
diphenolase |
38,39,50, 51,54,55 |
|
6,7,4'-Trihydroxyisoflavone |
hydroxyflavone |
monophenolase |
41 |
|
Daidzein, glyasperin C, formononetin, genistein, mirkoin, texasin, tectorigenin, odoratin |
Isoflavone |
|
45 |
|
Eriodictyol, naringenin, hesperetin, hesperidin, liquiritin naringin, taxifolin, 6-isoprenoid flavanone, nigrasin K, sanggenon M/C/O, chalcomoracin, kuwanon J, sorocein H |
flavanone |
|
48,49 |
|
Curcumin, desmethoxycurcumin, hydroxybenzoate, hydoxycinnamate |
phenolic compound |
|
57 |
|
Esculetin, 8-epi-cleomiscosin, umbelliferone, thiophosphonic acid diamide, diazaphosphinane, resveratrol-hybrid |
coumarin |
|
58-61 |
|
Butein, chalcone, flavan-3,4-diols, dihydroflavone, dihydrochalcone, 1,3-diphenyl-2-propen-1-one, carthamin, phloretin, sappan-chalcone, isoliquiritigenin, glabrene, 2,4,2,4-hydroxycalcone, 2,4,2′,4′-tetrahydroxychalcone 2,4,2',4'-tetrahydroxy-3-3-methyl-2-butenyl-chalcone, vulpinoideol-B, dihydrochalcone, morachalcone-A, bavachinin |
chalcone |
|
34,62 |
|
2-Arylbenzofuran, 2R-2,3-dihydro-2-1-hydroxy-1-methylethyl-2,6-bibenzofuran-6,4-diol, benzofuran flavonoid mulberrofuran G, albanol B, macrourins E |
aurone |
|
65,66 |
|
Resveratrol, oxyresveratrol, azo-resveratrol, azo-oxyresveratrol, E-2-2,4-dihydroxyphenyl, diazinyl, phenyl-4-methylbenzenesulfonate, trans-resveratrol, resveratrol dimer gnetin-C, hydroxystillbene |
stilbenes |
|
56,73-77 |
|
Monoterpenoid phenol, carvacrol aand its derivatives, bakuchiol, iridoid glucoside, sylvestrosyl 7-O-caffeoyl-I, sylvestrosyl 7-O-p-coumaroyl-I |
terpenoid |
|
79 |
In line 397,
Table 2. Summarization of the uncompetitive tyrosinase inhibitors
|
ompounds |
Property |
Uncompetitive type |
Reference |
|
Deoxyarbutin |
1, |
||
|
Luteolin |
|
diphenolase |
87 |
|
2,5-Dihydroxyacetophenone (DHAP), 2,6-DHAP |
|
90 |
|
|
β-D-Glucosyl 3,4-dihydroxy-5-methoxybiphenyl-2-O |
|
|
91 |
|
β-D-Glucosyl Ov-16-4-3,4-dihydroxybenzoyloxymethyl phenyl-O |
phenolic glycoside |
|
92 |
|
Sophorcarpidine |
flavonoid glycosides |
30 |
In line 427,
Table 3. Summarization of the mixed competitive and uncompetitive tyrosinase inhibitors
|
Compounds |
Property |
Mixed type |
Reference |
|
Cinnamic acid, aloin, hydroxypyridinone derivatives, phthalic acid derivatives |
93 |
||
|
D-Arabinose, brazilein and thymol derivatives |
|
diphenolase |
96,97 |
|
Baicalein |
|
98 |
|
|
Proanthocyanidin, procyanidin, prodelphinidin, propelargonidin, and the acyl derivatives (galloyl benzoate, p-hydroxybenzoate |
tannin |
|
99 |
|
3-Phenylbenzoic acid |
pheloic acid |
|
100 |
|
2-S-Lipoyl-CA |
CA-dihydrolipoic acid S-conjugate |
|
101 |
|
Isosilybin A/B, silydianin, 2,3-dihydrosilychristin, silybin, silychristin-A/-B |
flavonolignan |
monophenolase/diphenolase |
102 |
In line 483,
Table 4. Summarization of the noncompetitive tyrosinase inhibitors
|
Compounds |
Property |
Noncompetitive type |
Reference |
|
Barbarin, propanoic acid |
noncompetitive |
11 |
|
|
7,8,4-Trihydroxyflavone |
|
diphenolase |
109 |
|
8-Prenylkaempferol derivative Kushenol A, glabridin, 3,4-dihydroglabridin |
isoflavone |
|
110 |
|
p-Coumaric acid ethyl ester |
|
|
112 |
|
4-Substituted resorcinol |
|
|
111 |
|
Alkynyl glycoside analogues |
|
|
113 |
|
Caffeine |
|
|
114 |
|
Verbascoside and 2,4-dihydroxy-1,4-benzoxazin-3-one |
|
|
115 |
|
Betulinic acid |
|
|
116 |
|
3-O-α-l-Rhamnosyl-2-gallate quercetin, biflavanols, potenserin-C/-D, 3-O-α-l-rhamnosyl-2-gallate quercetin, biflavanol |
|
reversible/noncompetitive |
116,117 |
|
Polydatin, (-)-8-chlorocatechin, polydatin |
|
|
1118 |
|
4-Phenylsulfanyl butan-2-one, 2-acetyl-5-methoxyphenyl-3-4-hydroxyphenyl acrylate, benzaldehyde |
marine natural products |
diphenolase |
104,119,120 |
|
Oxyresveratrol, mulberroside A |
marine natural products |
diphenolase |
121 |
|
Mallotophilippen A, B |
marine natural products |
monophenolase |
122 |
|
6-Oxocyclohex-1-en-1-yl ethyl acetate |
marine natural products |
|
123 |
In line 483,
Table 4. Summarization of the noncompetitive tyrosinase inhibitors
|
Compounds |
Property |
Noncompetitive type |
Reference |
|
Barbarin, propanoic acid |
noncompetitive |
11 |
|
|
7,8,4-Trihydroxyflavone |
|
diphenolase |
109 |
|
8-Prenylkaempferol derivative Kushenol A, glabridin, 3,4-dihydroglabridin |
isoflavone |
|
110 |
|
p-Coumaric acid ethyl ester |
|
|
112 |
|
4-Substituted resorcinol |
|
|
111 |
|
Alkynyl glycoside analogues |
|
|
113 |
|
Caffeine |
|
|
114 |
|
Verbascoside and 2,4-dihydroxy-1,4-benzoxazin-3-one |
|
|
115 |
|
Betulinic acid |
|
|
116 |
|
3-O-α-l-Rhamnosyl-2-gallate quercetin, biflavanols, potenserin-C/-D, 3-O-α-l-rhamnosyl-2-gallate quercetin, biflavanol |
|
reversible/noncompetitive |
116,117 |
|
Polydatin, (-)-8-chlorocatechin, polydatin |
|
|
1118 |
|
4-Phenylsulfanyl butan-2-one, 2-acetyl-5-methoxyphenyl-3-4-hydroxyphenyl acrylate, benzaldehyde |
marine natural products |
diphenolase |
104,119,120 |
|
Oxyresveratrol, mulberroside A |
marine natural products |
diphenolase |
121 |
|
Mallotophilippen A, B |
marine natural products |
monophenolase |
122 |
|
6-Oxocyclohex-1-en-1-yl ethyl acetate |
marine natural products |
|
123 |
were newly written.
3- Discussion of the activity within the standard activity margins needs to be discussed.
As described, the standard activity has partly been discussed because the tyrosinase activity inhibitors are well reviewed in many different publications.
4- Classification of the inhibitors according to the chemical class and SARS will be helpful/interesting to the reader.
As described, Classification of the inhibitors according to the chemical class and SARS have well been reviewed in many independent review articles. However, the present review aims to summarize its inhibitory mechanism(s)-based classification.
5- The authors need to be careful and match between different names of the same molecule (lines 129/135; vitamin C = L-ascorbic acid), and correctly discuss the same, also in line 134, arbutin was mentioned twice.
As described, vitamin C has been corrected to L-ascorbic acid through the text. hydroquinone arbutin has been deleted.
6- The paragraph, between lines 132-137, needs careful re-phrasing.
As described, the lines 132-137 has been re-phrased.
Tyrosinase inhibitors have been purified from plants and kinetic tyrosinase inhibition studies using mushroom tyrosinases.
Currently known skin-whitening and anti-melanin molecules include arbutin, deoxyarbutin, hydroquinone, deoxyarbutin derivatives, resorcinol, vanillin, niacinamide, kojic acid, arbutin-mimic isotachioside, hydroquinon deribvatives (α and β-arbutin), azelaic acid, L-ascorbic acid, ellagic acid and tranexamic acid
7- Line 150, please correct and re-phrase.
As described, the line 150 has been corrected.
Inhibition of melanin biosynthesis reflects therapeutic and preventive options for melanogenesis. Tyrosinase inhibitors from natural products bind to the tyrosinases and the monophenolic tyrosinase (Fig. 3). Strategic approaches for reducing the level of melanin levels in dermal-epidermal junctional skin have been described with different ways of direct enzyme inhibitors and gene downregulators.
8- Line 154, check the typos.
As described, the line 154 has been corrected. Tyrosinase uses L-tyrosine and diphenolic L-DOPA as substrates
9- please write L-DOPA correctly.
As described, l-DOPA has been corrected to diphenolic L-DOPA
10- line 156, please correct the chemical name, and many more in the text.
As described, lone 56 has been corrected.
The met-tyrosinase catalyzes as diphenolase that oxidizes diphenol like L-DOPA to quinone and monophenolase that oxidizes monophenol like L-tyrosine to quinone like L-dopaquinone, although tyrosinase activity is generally measured using its substrate L-DOPA.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments for author File: Comments.pdf
Author Response
Thank you for the reviewer 2 for his(her) careful reading of out manuscript. The present review mainly focuses on the action mechanisms of tyrosinase inhibitors, but not introductory review because there are numerous reviews available from the literature.
Line 19. In vitro has been italicized to “
Line 60. “Procucr” has been corrected to “produce”
Figure 1: it has been re-figured to a new one
Line 98. “Whitening agent development is consists of” has been corrected to “Whitening agent development consists of”
Line 100. “Cu2+” has been corrected to “Cu2+”
Line 101. “NO” and “GM-GSF” in line 102
Line 122. via has been italicized to
Line 154. I-DOPA” has been corrected to “L-DOPA”
The writing has been coherent through the manuscript.
Line 228. “inhibitorory” has been corrected to “inhibitory”
Line 351. The bold “terpenoid” has been corrected to “terpenoid”.
Main molecular structures have been drawn
Line 515. “in silico” has been italicized to
Line 540. “in vitro” has been italicized to
Round 2
Reviewer 1 Report
Dear Authors, thanks for the correction, please check the comments below:
Figure 1. contains the wrong structures and should be re-drawn correctly
The chemical names should be corrected, C, p and O should be in italics (such as 3-O-β- 251 galactosyl quercetin, 3',5'-Di-C-β glucosyl phloretin // sylvestrosyl 7-O-p-coumaroyl-I), please check Table 1 as well.
table 1, the second column should be the class of compounds, not property. Also, it will be good to classify the structures according to the function of the class of compound. the current presentation is random. please check the typos in the table.
Tables 2, 3 and 4 contain typos and wrong and incomplete names
Author Response
2nd Responses to Reviewer and corrections
Dear Reviewers and Editor
(Separately uploaded 2nd response is available from the files)
Thank you for your careful checking of our revised version. We have carefully checked the content for writing style, chemical names, chemical structures, abbreviations, and English.
Questions
Figure 1. contains the wrong structures and should be re-drawn correctly
My Answer:
I am sorry for the tyrosine-modified structures and slightly corrected with redrawing..
The chemical names should be corrected, C, p and O should be in italics (such as 3-O-β- 251 galactosyl quercetin,
My Answer:
I am sorry for the uncareful writing in the compounds. The compound names are re-checked. For example, methoxy-hydroquinone-1-O-bD-glucopyranoside, 3-O-β-galactosyl quercetin, 3',5'-Di-C-β glucosyl phloretin and galactosyl-3-myricetin, Potenserin C and 3-O-α-L-rhamnosyl quercetin-2-gallate, 4'-O-b-D-glucosyl quercetin, β-D-glucosyl 3-O-6-O-malonyl quercetin, β-D-glucosyl 3-O-6-O-malonyl-kaempferol, sylvestrosyl 7-O-caffeoyl-I, sylvestrosyl 7-O-p-coumaroyl-I, , p-hydroxybenzoate, 3-O-α-l-Rhamnosyl-2-gallate quercetin, biflavanols, potenserin-C/-D, 3-O-α-l-rhamnosyl-2-gallate quercetin
table 1, the second column should be the class of compounds, not property. Also, it will be good to classify the structures according to the function of the class of compound. the current presentation is random. please check the typos in the table.
My Answer: As suggested, the property has been corrected to the Compound class through the Table 1- 5.
Tables 2, 3 and 4 contain typos and wrong and incomplete names
My Answer: As suggested, the typos and names have been re-checked. The examples: flavonoid glycoside (Table 2). phenolic acid (Table 3), noncompetitive removed (Table 4).
Editorial Question of Graphic abstract correction.
As suggested, the Graphic abstract has been redrawed.
Author Response File: Author Response.pdf
