Abstract
The pigments found in plants, animals and humic substances are well described and classified. In humans considerable progress has been made with the main pigment melanin in defining its biochemistry, the different types and function. However, analytical techniques to show these differences in vivo are still not readily available. NMR and IR spectroscopy are relatively insensitive and reveal only major structural differences. Techniques utilising MS are useful in determining elemental content but require further studies to optimise conditions for accurate mass analysis. How the components may be structurally organised seems to be the most problematic with scanning TEM and the improved FTIR of use in this respect. As regards understanding the nature of the pigment related to HGA seen in patients with Alkaptonuria (AKU), it is still thought of as a melaninlike pigment simply because of its colour and likewise thought to be a polymer of undetermined size. It is important that detailed analysis be carried out to define more accurately this pigment. However, observations suggest it to be the same as the HGA-derived pigment, pyomelanin, produced by bacteria and containing both quinone and phenolic groups. The interesting developments in alkaptonuria will be to understand how such a polymer can cause such profound collagen and connective tissue damage and how best to reverse this process.
Keywords
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Competing interests: None declared
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Baker MJ, Trevisan J, Bassan P et al (2014) Using Fourier transform IR spectroscopy to analyze biological materials. Nature Prot 9:1771–1791
Bancroft JD, Stevens A (1955) Theory and practice of histological techniques, 2nd edn. Churchill Livingstone, New York
Barber TM, Adams E, Ansorge O, Byrne JV, Karavitaki N, Wass JAH (2010) Review Nelson’s syndrome. Eur J Endo 163:495–507
Bender RP, Ham AJL, Osheroff N (2007) Quinone-induced enhancement of DNA cleavage by human topoisomerase IIα: adduction of cysteine residues 392 and 405. Biochem 46:2856–2864
Berson JF, Harper DC, Tenza D, Raposo GA, Marks MS (2001) Pmel17 initiates premelanosome morphogenesis within multivesicular bodies. Molec Biol Cell 12:3451–3464
Braconi D, Laschi M, Amato L, Bernardini G, Millucci L, Marcolongo R, Cavallo G, Spefico A, Santucci A (2010) Evaluation of anti-oxidant treatments in an in vitro model of alkaptonuric ochronosis. Rheum 49:1975–1983
Braconi D, Bianchini C, Bernardini G, Laschi M, Millucc L, Spreafico A, Santucci A (2011) Redox-proteomics of the effects of homogentisic acid in an in vitro human serum model of alkaptonuric ochronosis. J Inherit Metab Dis 34:1163–1176
Bush WD, Gargullo J, Zucca FA et al (2006) The surface oxidation potential of human neuromelanin reveals a spherical architecture with a pheomelanin core and a eumelanin surface. PNAS 103:14785–14789
Carreira A, Ferreira LM, Loureiro V (2001) Brown pigments produced by Yarrowia lipolytica result from extracellular accumulation of homogentisic acid. Appl Environ Microbiol 67:3463–3468
Chen C-T et al (2014) Excitonic effects from geometric order and disorder explain broadband optical absorption in eumelanin. Nat Commun 5:3859–3866
Childs A, Jacobs C, Kaminski T, Halliwell B, Leeuwenburgh C (2001) Supplementation with vitamin C and N-acetyl- cysteine increases oxidative stress in humans after an acute muscle induced by eccentric exercise. Free Rad Biol Med 31:745–753
Cichorek M, Wachulska M, Stasiewicz A, Tymińska A (2013) Skin melanocytes: biology and development. Postep Derm Alergol 30:30–41
D’Ischia M, Wakamatsu K, Napolitano A et al (2013) Melanins and melanogenesis: methods, standards, protocols. Pig Cell Melan Res 26:616–633
David C, Daro A, Szalai E, Atarhouch T, Mergeay M (1996) Formation of polymeric pigments in the presence of bacteria and comparison with chemical oxidative coupling-II. Catabolism of tyrosine and hydroxyphenylacetic acid by Alcaligenes eutrophus CH34 and mutants. Eur Polym J 32:669–697
Del Marmol V, Beermann F (1996) Tyrosinase and related proteins in mammalian pigmentation. FEBS Lett 381:165–168
Delgado-Vargas F, Jiménez AR, Paredes-López O (2000) Natural pigments: carotenoids, anthocyanins, and betalains — characteristics, biosynthesis, processing, and stability. Crit Revs Food Sci Nutr 40(3):173–289
Ellis DH, Griffiths DA (1974) The location and analysis of melanins in cell walls of some soil fungi. Canad J Micro 20:1379–1386
Eslami M, Zare HR, Namazia M (2014) The effect of solvents on the electrochemical behaviour of homogentisic acid. J Electrchem 720:76–83
Figueras LE, Rodriguez-Catellanos MA, Gonzalez-Mendoza A, Cantu JM (1993) Hyperkeratosis-hyperpigmentation syndrome: a confirmative case. Clin Genet 43(2):73–75
Forslind B, Roomans GM, Carlsson LF, Malmquist KG, Akselsson KR (1984) Elemental analysis on freeze-dried sections of human skin: studies by electron microscopy and particle induced X-ray emission analysis. Scann Elec Micro 11:755–759
FP7-HEALTH (2012) DEVELOPAKURE: clinical development of nitisinone for alkaptonuria; Project reference: 304985 Cordis.europ.eu/project/rcn/106157
Frases S, Salazar A, Dadachova E, Casadeval A (2007) Cryptococcus neoformans can utilize the bacterial melanin precursor homogentisic acid for fungal melanogenesis. Appl Environ Micro 73:615–621
Galasso V, Pichierri F (2009) Probing the molecular and electronic structure of norhipposudoric and hipposudoric acids from the red sweat of hippopotamus amphibius: a DFT investigation. J Phys Chem A 113(11):2534–2543
Hashimoto K, Saikawa Y, Nakata M (2007) Studies on the red sweat of the Hippopotamus amphibius. Pure Appl Chem 79(4):507–517
Hegedus ZL (2000) The probable involvement of soluble and deposited melanins their intermediates and reactive oxygen side products in human disease and ageing. Toxic 145:85–101
Introne WJ, Perry MB, Troendle J et al (2011) A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab 103(4):307–314
Ito S, Wakamatsu K (2008) Chemistry of mixed melanogenesis–pivotal roles of dopaquinone. Photochem Photobiol 84(3):582–592
Jablonski N (2012) Living color. University of California Press, Berkeley/Los Angeles/London
Jablonski NG, Chaplin G (2010) Colloquium paper: human skin pigmentation as an adaptation to UV radiation. PNAS 107:8962–8968
Kai M, Masanori M, Yoko S et al (2006) Properties of the enzyme responsible to the synthesis of hipposudoric acid and norhipposudoric acids, the pigments in the red sweat of the hippopotamus. Nippon Kagakkai Koen Yokoshu 86(2):1314–1318
Kassinger RG (2003) Dyes from sea snails to synthetics 21st century books. www.Millbrookpress.com
Kastyak-Ibrahim MZ, Nasse MJ, Rak M et al (2011) Biochemical label-free tissue imaging with subcellular-resolution synchrotron FTIR with focal plane array detector. Neuro Image 60(1):376–383
Keith KE, Killip L, He P, Moran GR, Valvano MA (2007) Burkholderia cenocepacia C5424 produces a pigment with antioxidant properties using a homogentisate intermediate. J Bacteriol 189:9057–9065
Keller JM, Macaulay W, Nercessian OA, Jaffe IA (2005) New developments in ochronosis: review of the literature. Rheum Int 25:81–85
Land EJ, Ramsden CA, Riley PA (2003) Tyrosinase autoactivation and the chemistry of ortho-quinone amines. Acc Chem Res 36(5):300–308
Laschi M, Tinti L, Braconi D et al (2012) Homogentisate 1,2 dioxygenase is expressed in human osteoarticular cells: implications in alkaptonuria. J Cell Physiol 227(9):3254–3257
Lee WC, Li LC, Chen JB, Chang HW (2015) Indoxyl sulfate-induced oxidative stress, mitochondrial dysfunction, and impaired biogenesis are partly protected by vitamin C and N-acetylcysteine. Sci World J 2015:620826
Levine N, Dorr RT, Ertl GA, Brooks C, Alberts DS (1999) Effects of a potent synthetic melanotropin, Nle4-D-Phe7alpha-MSH (Melanotan) on tanning: dose ranging study. J Dermatol Treat 10:127–132
Levy C, Khaled M, Fisher DE (2006) Review MITF: master regulator of melanocyte development and melanoma oncogene. Trends in Molec Med 12:406–414
Littrell KC, Gallas JM, Zajac GW, Thiyagarajan P (2003) Structural studies of bleached melanin by synchrotron small-angle X-ray scattering. Photochem Photobiol 77:115–120
Liu SY, Shawkey MD, Parkinson D, TroyTP AM (2014) Elucidation of the chemical composition of avian melanin. RSC Adv 4:40396–40399
Lok ZS, Goldstein J, Smith JA (2013) Alkaptonuria-associated aortic stenosis. J Card Surg 28:417–420
Martin JP, Batkoff B (1987) Homogentisic acid autooxidation and oxygen radical generation: implications for the etiology of Alkaptonuria arthritis. Free Rad Biol Med 3:241–250
Mentner LM, Willis I (1997) Electron transfer and photoprotective properties of melanins in solution. Pigm Cell Res 10:214–217
Millington GWM (2006) Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors. Clin Expt Dermat 31:407–412
Millucci L, Spreafico A, Tiniti A et al (2012) Alkaptonuria is a novel human secondary amyloidogenic disease. BBA Molec Basis Dis 1822:1682–1691
Millucci L, Ghezzi L, Paccagnini E et al (2014) Amyloidosis, inflammation, and oxidative stress in the heart of an alkaptonuric patient. Mediat Inflamm 12. Article ID 258471
Momohara S, Okamoto H, Yamanaka H (2008) Chondrocyte of rheumatoid arthritis serve as a source of intra-articular acute-phase serum amyloid A protein. Clin Chim Acta 398:155–156
Murisier F, Beermann F (2006) Genetics of pigment cells: lessons from the tyrosinase gene family. Histo Histopath 21(5):567–578
Nicolaus RA (1969) In: Lederer E (ed) Melanins chemistry of natural products. Hermann, Paris
Nordlund JJ, Boissy R, Hearing VJ, King RA (2006) In: Oetting W, Ortonne J-P (eds) The pigmentary system, 2nd edn. Blackwell, Oxford, 1229 pp
Novotny NR, Capley EN, Stenson AC (2014) Fact or artifact: the representativeness of ESI-MS for complex natural organic mixtures. J Mass Spect 49:316–326
Ogunnariwo J, Hamilton-Miller MT (1975) Brown and red pigmented Pseudomonas aeruginosa differentiation between melanin and pyrorurin. J Med Microbiol 8:199–203
Pallotta V, Gevi F, D'Alessandro A, Zolla L (2014) Storing red blood cells with vitamin C and N-acetylcysteine prevents oxidative stress-related lesions: a metabolomics overview. Blood Transfus 12:367–387
Peña-Méndez EM, Josef Havel J, Patočka J (2005) REVIEW Humic substances compounds of still unknown structure:applications in agriculture, industry, environment, and biomedicine. J Appl Biomed 3:13–24
Phornphutkul C, Introne WJ, Perry MB et al (2002) Natural history of alkaptonuria. N Engl J Med 347:2111–2121
Phornphutkul C, IntroneWJ, Way P, William A, Gahl WA (2003) Alkaptonuria. N Engl J Med 348:1408
Preston AJ, Keenan CM, Sutherland H et al (2014) Chronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone. Ann Rheum Dis 73:284–289
Pritchard LE, Turnbull AV, White A (2002) Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity. J Endo 172:411–421
Przemyslaw M, Plonka L, Grabacka M (2006) Review Melanin synthesis in microorganisms – biotechnological and medical aspects. Acta Biochim Pol 53:429–443
Ranganath LR, Jarvis JC, Gallagher JA (2013) Recent advances in management of alkaptonuria (invited review, best practice article). J Clin Pathol 66(5):367–373
Ranganath LR, Milan AM, Hughes AT (2014) Suitability of nitisinone in alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment. Ann Rheum Dis. doi:10.1136/annrheumdis-2014-206033
Ruzafa C, Sanchez-Amat A, Solano F (1995) Characterization of the melanogenic system in Vibrio cholerae, ATCC 14035. Pigment Cell Res 8(3):147–152
Sakamoto K, Liu C, Kasamatsu M, Pozdeyv NV, Iuvone PM, Tosini G (2005) Dopamine regulates melanopsin mRNA expression in intrinsically photosensitive retinal ganglion cells. Eur J Neurosci 22(12):3129–3136
Solano F (2014) Melanins: skin pigments and much more – types, structural models, biological functions, and formation routes. New J Sci 28. doi:10.1155/2014/498276. Article ID 498276
Stuart JA, Brige RR (1996) Characterization of the primary photochemical events in bacteriorhodopsin and rhodopsin. In: Lee AG (ed) Rhodopsin and G-protein linked receptors, part A, vol 2. JAI Press, Greenwich, pp 33–140
Sulzer D, Zecca L (1999) Intraneuronal dopamine-quinone synthesis: a review. Neurotox Res 1:181–195
Sutton R, Sposito G (2005) Molecular structure in soil humic substances: the new view. Environ Sci Technol 39(23):9009–9015
Suzuki Y, Oda K, Yoshikawa Y, Maeda Y, Suzuki T (1999) A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria. J Hum Genet 44(2):79–84
Takeda K, Takahashi NH, Shibahara S (2007) Neuroendocrine functions of melanocytes: beyond the skin-deep melanin maker. Tohuku J Exp Med 211(3):201–221
Thureau P, Ziarelli F, Thvand A et al (2012) Probing the motional behavior of eumelanin and pheomelanin with solid-state NMR spectroscopy: new insights into the pigment properties. Chemta Indicat Eur J 18:10689–10700
Tinti L, Spreafico A, Braconi D, Millucci L, Bernardini G, Chellini F, Cavallo G, Selvi E, Galeazzi M, Marcolongo R, Gallagher JA, Santucci A (2010) Evaluation of antioxidant drugs for the treatment of ochronotic alkaptonuria in an in vitro human cell model. J Cell Physiol 225:84–91
Tokuhara Y, Shukuya K, Tanaka M et al (2014) Detection of novel visible-light region absorbance peaks in the urine after alkalization in patients with alkaptonuria. PLoS One 9(1):e86606
Tran ML, Powell BJ, Meredith P (2006) Chemical and structural disorder in eumelanins: a possible explanation for broadband absorbance. Biophys J 90:743–752
Tribl F, Gerlach M, Marcus K et al (2005) Subcellular proteomics of neuromelanin granules isolated from the human. Brain Molec Cell Proteom 4:945–957
Turick CE, Tisa LS, Caccavo F Jr (2002) Melanin production and use as a soluble electron shuttle for Fe(III) oxide reduction and as a terminal electron acceptor by Shewanella algae BrY. Appl Environ Microbiol 68:2436–2444
Turick, CE, Caccavo F Jr, Tisa LS (2003) Electron transfer to Shewanella algae BrY toHFO is mediated by cell-associated melanin. FEMS Microbiol Lett 220:99–104
Turick CE, Beliaev A, Ekechukwu AA, Poppy T, Maloney A, Lowy DA (2009) The role of 4-hydroxyphenylpyruvate dioxygenase in enhancement of solid-phase electron transfer by Shewanella oneidensis MR-1. FEMS Microbiol Ecol 68:223–235
Turick CE, Knox AS, Becne JMl, Ekechukwu AA, Milliken CE (2010) Properties and function of pyomelanin. In: Elnashar MM (ed) Biopolymers. Sciyo Janeza Trdine, Croatia, Chap. 26
Valverde P, Healy E, Jackson I, Rees JL, Thody AJ (1995) Variants of the melanocyte – stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nature Genet 11(3):328–330
Venkataraman K (ed) (2012) The chemistry of synthetic dyes. Elsevier, London
Videria IFS, Moura DFL, Magina S (2013) Mechanisms regulating melanogenesis. An Bras Dermatol 88(1):76–83
Wakamatsu K, Hu DN, McCormick SA, Ito S (2008) Characterization of melanin in human iridal and choroidal melanocytes from eyes with various colored irides. Pig Cell Melan Res 21(1):97–105
Watt AAR, Bothma JP, Meredith P (2009) The supramolecular structure of melanin. Soft Matter 5:3754–3760
Williams DP, Lawrence A, Meng X (2012) Pharmacological and toxicological considerations of homogentisic acid in alkaptonuria. Pharmacology 3:61–74
Wolff JA, Barshop B, Nyhan WL et al (1989) Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy. Pediatr Res 26:140–144
Zannoni VG, Lomtevas N, Goldfinger SO (1969) Oxidation of homogentisic acid to ochronotic pigment in connective tissue. Biochim Biophys Acta 177:94–105
Zecca L, Bellei C, Costi P et al (2008) New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals. PNAS 105:17567–17572
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Jörn Oliver Sass
Appendices
Compliance with Ethics Guidelines
All procedures reported in this review were in accordance with the ethical standards of the local hospital ethics committee and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from patient(s) wherever included in this review.
Conflict of Interest
NB Roberts, SACurtis, A Milan and LR Ranganath have no conflict of interest.
NB Roberts was the main author who reviewed the literature and completed the review.
SA Curtis was responsible for the UV–visible spectra.
AM Milan, a senior colleague in the AKU group, reviewed and made corrections to the manuscript.
LR Ranganath is the director of the AKU group and was responsible for the commissioning of this review and made corrections to the manuscript.
Rights and permissions
Copyright information
© 2015 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Roberts, N.B., Curtis, S.A., Milan, A.M., Ranganath, L.R. (2015). The Pigment in Alkaptonuria Relationship to Melanin and Other Coloured Substances: A Review of Metabolism, Composition and Chemical Analysis. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 24. JIMD Reports, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_453
Download citation
DOI: https://doi.org/10.1007/8904_2015_453
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-48226-1
Online ISBN: 978-3-662-48227-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)