The high serum concentration of albumin is due to its rate of synthesis, that takes place mainly in the liver, to its size, and to its interaction with the neonatal Fc receptor, abbreviated FcRn. FcRn is a cellular receptor widely expressed in several organs and tissues. Albumin has a prolonged serum half-live of 19 days, compared with a few days or less for other circulating proteins. FcRn is a dual binding receptor that, in addition to albumin, binds IgG, and protects both proteins from intracellular degradation. Thus, FcRn has a pivotal role in prolonging their serum half-lives. [Andersen, J.T., Dalhus, B., Viuff, D., Ravn, B.T., Gunnarsen, K.S., Plumridge, A., Bunting, K., Antunes, F., Williamson, R., Athwal, S., Allan, E., Evans, L., Bjørås, M., Kjærulff, S., Sleep, D., Sandlie, I. & Cameron, J. (2014) Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding. J. Biol. Chem. 289, 13492-13502]. FcRn is a non-classical major class I histocompatibility molecule that consists of a unique transmembrane heavy chain that is non-covalently associated with the common β2-microglobulin. It is predominantly localized in acidic endosomal compartments and binds albumin or IgG molecules in a pH-dependent manner so that the strength of the corresponding interactions ranges from highest at acidic pH (pH 6.0) to lowest around neutral pH. This remarkable property is critical to recycling IgG and albumin from within acidic endosomes back to the general circulation and allows their rescue from a degradative pathway. In fact, FcRn-ligand complexes are exported to the cell surface, where exposure to the higher physiological pH of the bloodstream triggers release of the ligands by a so-called kiss-and-run exocytotic mechanism. [Andersen, J.T., Dalhus, B., Cameron, J., Daba, M.B., Plumridge, A., Evans, L., Brennan, S.O., Gunnarsen, K.S., Bjørås, M., Sleep, D. & Sandlie, I. (2012) Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor. Nat. Commun. 3, Article number: 610]. This recycling was stated to save as much albumin from degradation as the liver produces [Kim, J., Bronson, C.L, Hayton, W.L., Radmacher, M.D., Roopenian, D.C., Robinson, J.M. & Anderson, C.L. (2006) Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces. Am. J. Physiol. 290, G352-G360]. Two siblings lacking the FcRn were described as "markedly deficient in albumin and IgG" [Wani, M.A., Haynes, L.D., Kim, J., Bronson, C.L., Chaudhury, C., Mohanty, S., Waldmann, T.A., Robinson, J.M. & Anderson, C.L. (2006) Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. Proc. Nat. Acad. Sci. USA 103, 5084-5089]. The C-terminal domain of the albumin molecule has been shown to be crucial for binding to FcRn. Lack of domain IIIB or mutations of 464His, 510His and 535His almost completely abolish FcRn binding [Andersen, J.T., Dalhus, B., Cameron, J., Daba, M.B., Plumridge, A., Evans, L., Brennan, S.O., Gunnarsen, K.S., Bjørås, M., Sleep, D. & Sandlie, I. (2012) Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor. Nat. Commun. 3, Article number: 610]. The three-dimensional structure of human FcRn bound concurrently to its two known ligands has been recently elucidated [Oganesyan, V., Damschroder, M.M., Cook, K.E., Li, Q., Gao, C., Wu, H. & Dall'Acqua, W.F. (2014) Structural insights into neonatal Fc receptor-based recycling mechanisms. J. Biol. Chem. 289, 7812-7824].
The metabolism of plasma albumin was studied in one-day old preterm infants with a stable isotope [1-13C]leucine, showing that liver synthetic capacity is well developed in very low birth weight infants. [Bunt, J.E., Rietveld, T., Schierbeek, H., Wattimena, J.L., Zimmermann, L.J. & van Goudoever, J.B. (2007) Albumin synthesis in preterm infants on the first day of life studied with [1-13C]leucine. Am. J. Physiol. 292, G1157-1161]. The study of albumin synthesis rates during early life under physiologic circumstances showed that the fractional synthesis rate of albumin in 28-35-week premature infants was 17.5%/day, but only 10.4%/day in term infants [van den Akker, C.H., Schierbeek, H., Rietveld, T., Vermes, A., Duvekot, J.J., Steegers, E.A. & van Goudoever, J.B. (2008) Am. J. Clin. Nutr. 88, 997-1003]. The kinetics of both albumin and alpha-fetoprotein synthesis in the developing rat liver was followed using radioactive biosynthetic labeling of newly synthesized proteins. The model used suggested that the hepatocyte secretory apparatus is already functional before the emergence of the liver bud [Elmaouhoub, A., Dudas, J. & Ramadori, G. (2007) Kinetics of albumin- and alpha-fetoprotein-production during rat liver development. Histochem. Cell Biol. 128, 431-433].
Albumin expression was reported in many non-hepatic tissues. Examples may be:
(1) Apparent production of the rat albumin phenotype was observed in cultures of healing rat bones, suggesting that albumin plays an important role in the promoting of fracture repair. [Yamaguchi, M., Igarashi, A., Misawa, H. & Tsurusaki, Y. (2003) Enhancement of albumin expression in bone tissues with healing rat fractures. J. Cell. Biochem. 89, 356-363].
(2) Expression of bovine albumin mRNA was observed at a low level in many non-hepatic tissues: intestine, lymph gland, testicle, uterus, tongue, and mammary gland [Shamay, A., Homans, R., Fuerman, Y., Levin, I., Barash, H., Silanikove, N. & Mabjeesh, S.J. (2005) Expression of albumin in nonhepatic tissues and its synthesis by the bovine mammary gland. J. Dairy Sci. 88, 569-576].
(3) Frog (Bombina maxima) albumin was shown to be expressed in skin and to inhibit trypsin [Zhang, Y.X., Lai, R., Lee, W.H. & Zhang, Y. (2005) Frog albumin is expressed in skin and characterized as a novel potent trypsin inhibitor. Protein Sci. 14, 2469-2477].
The rate of albumin synthesis is dependent on nutritional status, especially on the extent of amino acid deficiencies. However, the synthesis and secretion of albumin is also influenced by other factors. For example, administration of recombinant growth hormone in patients with chronic liver failure causes an increase in albumin concentration and raised the survival at 6 months from 14% to 55% [Li, N., Zhou, L., Zhang, B., Dong, P., Lin, W., Wang, H., Xu, R. & Ding, H. (2008) Recombinant human growth hormone increases albumin and prolongs survival in patients with chronic liver failure: A pilot open, randomized, and controlled clinical trial. Dig. Liv. Dis, 40, 554-558].
All-trans retinoic acid, which is a major bioactive metabolite of vitamin A and a potent regulator of development and differentiation, mediates down-regulation of the human albumin gene [Masaki, T., Matsuura, T., Ohkawa, K., Miyamura, T., Okazaki, I., Watanabe, T. & Suzuki, T. (2006) All-trans retinoic acid down-regulates human albumin gene expression through the induction of C/EBPbeta-LIP. Biochem. J. 397, 345-353]. Interleukin 6 and tumor necrosis factor TNF-α, but not interleukin 10 or the drug tacrolimus, suppress hepatic albumin secretion [Li, Y., Liu, F.-Y., Liu, Z.-H., Huang, Y.-F., Li, L.-S., Zhang, X. & Peng, Y.-M. (2006) Effect of tacrolimus and cyclosporine A on suppression of albumin secretion induced by inflammatory cytokines in cultured human hepatocytes. Inflamm. Res. 55, 216-220]. Also high doses of cyclosporine A can inhibit hepatic albumin synthesis at the level of translation [Jeon, Y.J. & Kim, Y.S. (2011) Cyclosporin A inhibits albumin synthesis in Huh7 cells. Korean J. Intern Med. 26, 314-319]. However, also other factors such as malnutrition can decrease the rate of albumin synthesis. Finally, low and very low albumin concentrations in the circulation can be the result of analbuminemia (see REGISTER OF ANALBUMINEMIA CASES).
Bar-Or et al. have examined albumin in plasma from 27 normal subjects by mass spectrometry and found the forms quantified in the table. They also detected pronounced heterogeneity in commercial samples of human serum albumin [Bar-Or, D., Bar-Or, R., Rael, L.T., Gardner, D.K., Slone, D.S. & Craun, M.L. (2005) Heterogeneity and oxidation status of commercial human albumin preparations in clinical use. Crit. Care Med. 33, 1638-1641].
Range of six commercial preparations
26.3 – 29.8%
21.9 – 29.3%
+NO at Cys-SH
11.4 – 13.8%
Total bound to half-Cys
55.4 – 60.3%
Half-Cys glycated albumin
2.8 – 4.2%
Native minus N-term. Asp-Ala
3.6 – 8.2%
Native minus C-term. Leu
3.0 – 5.6%
The small amounts of albumin lacking N-terminal or C-terminal residues were seen in all subjects and are of considerable metabolic interest (see later under Rapid Clearance of Albumin). The same authors have also identified dehydroalanine as a breakdown product of 487Cys [Bar-Or, R., Rael, L.T. & Bar-Or, D. (2008) Dehydroalanine derived from cysteine is a common post-translational modification in human serum albumin. Rapid Commun. Mass Spectrom. 22, 711-716]. The presence of the modified residue has potential effects on ligand binding, plasma clearance, protein-protein interactions and oxidation-reduction potential. Commercial albumin preparations all showed considerable oxidation of the free cysteine with the formation of S-S bound ligands. Lot-to-lot variability of the mercaptalbumin percentage in 3 commercial albumins was 4.8 – 11.2%. The cysteinylation of commercial human serum albumin has been further studied by two forms of mass spectrometry: Kleinova, M., Belgacem, O., Pock, K., Rizzi, A., Buchacher, A. & Allmaier, G. (2005) Characterization of cysteinylation of pharmaceutical-grade human serum albumin by electrospray ionization mass spectrometry and low-energy collision-induced dissociation tandem mass spectrometry. Rapid Commun. Mass Spectrom. 19, 2965-2973. However, it should be noted that the amount and type of modifications in commercial preparations can be affected by various parameters, such as time and temperature of storage [Berezenko, S. (2006) Comment on: Heterogeneity and oxidation status of commercial human albumin preparations in clinical use. Crit.Care Med. 34, 1291].
This finding applied to human albumin preparations containing stabilizers, such as caprylate (octanoate) and acetyl-tryptophan, added to avoid polymerization during pasteurization. However, the used stabilizers are bound to albumin binding site II in subdomain IIIA, and therefore the risk exists that transport functions of pasteurized albumin is impaired and after intravenous infusion endogenous albumin ligands may be displaced [Klammt, S., Brinkmann, B., Mitzner, S., Munzert, E., Loock, J., Stange, J., Emmrich, J. & Liebe, S. (2001) Albumin binding capacity (ABiC) is reduced in commercially available human serum albumin preparations with stabilizers. Z.Gastroenterol. 39 Suppl. 2, 24-27].
Commercial albumin preparations for clinical use were tested in vitro for their actions on cytokine release from activated human peripheral blood mononuclear cells and showed immunosuppressive effects. In view of these findings, administering albumin to immunocompromised critically ill patients might be reevaluated [Bar-Or, D., Thomas, G.W., Bar-Or, R., Rael, L.T., Scarborough, K., Rao, N. & Shimonkevitz, R. (2006) Commercial human albumin preparations for clinical use are immunosuppressive in vitro. Crit. Care Med. 34, 1707-1712].
Binding of fatty acids was shown to facilitate oxidation of cysteine-34 and to convert copper-albumin complexes from antioxidants to prooxidants [Gryzunov, Y.A., Arroyo, A., Vigne, J.L., Zhao, Q., Tyurin, V.A., Hubel, C.A., Gandley, R.E., Vladimirov, Y.A., Taylor, R.N. & Kagan, V.E. (2003) Binding of fatty acids facilitates oxidation of cysteine-34 and converts copper-albumin complexes from antioxidants to prooxidants. Arch. Biochem. Biophys. 413, 53-66]. Fatty acid binding increases the accessibility of 34Cys and thereby increases S-nitrosylation of the residue [Ishima, Y., Akaike, T., Kragh-Hansen, U., Hiroyama, S., Sawa, T., Maruyama, T., Kai, T. & Otagiri, M. (2007) Effects of endogenous ligands on the biological role of human serum albumin in S-nitrosylation. Biochem. Biophys. Res. Commun. 364, 790-795].
Conversion of the thiol of Cys-34 to sulfenic acid occurs and has metabolic functions. The most likely fate for sulfenic acid formed in the plasma environment is the reaction with low molecular weight thiols to form mixed disulfides, a reversible modification that is actually observed in ~25% of circulating albumin. Another possible fate for sulfenic acid is further oxidation to sulfinic and sulfonic acids. See the reviews: (1) Carballal, S., Alvarez, B., Turell, L., Botti, H., Freeman, B.A. & Radi. R. (2007) Sulfenic acid in human serum albumin. Amino Acids 32, 543-551; (2) Salsbury, F.R. Jr., Knutson, S.T., Poole, L.B. & Fetrow, J.S. (2008) Functional site profiling and electrostatic analysis of cysteines modifiable to cysteine sulfenic acid. Prot. Sci. 17, 299-312. (3) Alvarez, B., Carballal, S., Turell, L. Radi, R. (2010) Formation and reactions of sulfenic acid in human serum albumin. Methods Enzymol. 473, 117-136.
Patients with active focal segmental glomerulosclerosis were shown by a mass spectrometry technique to have oxidized plasma albumin because of the oxidation of Cys 34 to cysteic acid (Cys SO3−). The possibility to have readily available laboratory assays may lead to preemptive therapy before the development of massive proteinuria [Musante, L., Candiano, G., Petretto, A., Bruschi, M., Dimasi, N., Caridi, G., Pavone, B., Del Boccio, P., Galliano, M., Urbani, A., Scolari, F., Vincenti, F. & Ghiggeri, G.M. (2007) Active focal segmental glomerulosclerosis is associated with massive oxidation of plasma albumin. J. Am. Soc. Nephrol. 18, 799-810].
Human serum albumin was subjected to oxidative stress under metal-catalyzed oxidation (MCO) conditions or by treatment with hypochlorous acid (HOCl), and the locations of the resulting protein carbonyls were determined using mass spectrometry. Under MCO conditions, only two of the 59 lysine residues appeared to be modified (97Lys and 186Lys). With HOCl, five different lysine modification sites were identified (130Lys, 257Lys, 438Lys, 499Lys, and 598Lys) [Temple, A., Yen, T.Y. & Gronert, S. (2006) Identification of sites of carbonylation. Amer. Soc. Mass Spect. 17, 1172-1180]. Low concentrations of chloramine-T oxidize 34Cys and methionine residues; at higher concentrations the tryptophan residue also appears to be oxidized [Anraku, M., Kragh-Hansen, U., Kawai, K., Maruyama, T., Yamasaki, Y., Takakura, Y. & Otagiri, M. (2003) Validation of the chloramine-T induced oxidation of human serum albumin as a model for oxidative damage in vivo. Pharm. Res. 20, 684-692]. A study with recombinant albumins and a series of oxidizing agents showed in a direct way that 34Cys plays a more important role than the methionine residues in the antioxidant activity of albumin [Iwao, Y., Ishima, Y., Yamada, J., Noguchi, T., Kragh-Hansen, U., Mera, K., Honda, D., Suenaga, A., Maruyama, T. & Otagiri, M. (2012) Quantitative evaluation of the role of cysteine and methionine residues in the antioxidant activity of human serum albumin using recombinant mutants. IUBMB Life 64, 450-454]. Diabetes mellitus, liver diseases and nephropathy are just a few examples of disorders in which oxidative stress is involved, and altered albumin functions have been described. See the reviews: (1) Oettl, K. & Stauber, R.E. (2007) Physiological and pathological changes in the redox state of human serum albumin critically influence its binding properties. Brit. J. Pharmacol. 151, 580-590; (2) Anraku, M., Chuang, V.T.G., Maruyama, T. & Otagiri, M. (2013) Redox properties of serum albumin. Biochim. Biophys. Acta 1830, 5465-5472; (3) Bruschi, M., Candiano, G., Santucci, L. & Ghiggeri, G.M. (2013) Oxidized albumin. The long way of a protein of uncertain function. Biochim. Biophys. Acta 1830, 5473-5479.
Non-enzymatic glycation of albumin is associated with the long-term complications of diabetes. Mass spectrometry was used to determine the structures and locations of glycation adducts, allowing the identification of several specific lysine and arginine residues as modification sites. (1) Anguizola, J., Matsuda, R., Barnaby, O.S., Hoy, K.S., Wa, C., DeBolt, E., Koke, M. & Hage, D.S. (2013) Review: Glycation of human serum albumin. Clin. Chim. Acta 425, 64-76; (2) Wa, C., Cerny, R.L., Clarke, W.A. & Hage, D.S. (2007) Characterization of glycation adducts on human serum albumin by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Clin. Chim. Acta 385, 48-50. Work with recombinant mutants has shown that the effect of glycation can be partly explained by blockage of the positive charges of lysine at positions 199, 439 and 525 [Nakajou, K., Watanabe, H., Kragh-Hansen, U., Maruyama, T. & Otagiri, M. (2003) The effect of glycation on the structure, function and biological fate of human serum albumin as revealed by recombinant mutants. Biochim. Biophys. Acta 1623, 88-97]. In current clinical practice, long-term glycemic control is assessed by quarterly measurements of HbA1c. Since the degree of hemoglobin glycosylation depends not only on the level of glycemic control, but also on the lifespan of red blood cells, patients with hemoglobin disorders or anemia of any cause may have erroneous HbA1c levels, and consequently receive insufficient treatment. Patients with chronic kidney disease often suffer from various types of anemia, and, as a consequence, they are frequently treated with iron and/or erythropoietin therapy or frequent blood transfusion. This might cause underestimation of HbA1c owing to the presence of an increased proportion of young erythrocytes. (1) Inaba, M., Okuno, S., Kumeda, Y., Yamada, S., Imanishi, Y., Tabata, T., Okamura, M., Okada, S., Yamakawa, T., Ishimura, E. & Nishizawa, Y.; Osaka CKD Expert Research Group (2007) Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J. Am. Soc. Nephrol. 18, 896-903. (2) Zheng, C.M., Ma, W.Y., Wu, C.C. & Lu, K.C. (2012) Glycated albumin in diabetic patients with chronic kidney disease. Clin. Chim. Acta 413, 1555-1561. For additional reviews, see (1) Cohen, M.P. (2013) Clinical, pathophysiological and structure/function consequences of modification of albumin by Amadori-glucose adducts. Biochim. Biophys. Acta 1830, 5480-5485; (2) Furusyo, N. & Hayashi, J. (2013) Glycated albumin and diabetes mellitus. Biochim. Biophys. Acta 1830, 5509-5514.
Des-Leu albumin, the truncated form of albumin lacking the C-terminal leucine, is present at high concentration in pancreatitis, and can be measured by a liquid-chromatography tandem-mass spectrometry. Therefore, it has been proposed as a promising novel biomarker for chronic pancreatitis [Ireland, R.D., Brennan, S.O., Gerrard, J.A., Walmsley, T.A., George, P.M. & King, R.I. (2012) A mass-spectroscopic method for measuring des-Leu albumin--a novel marker for chronic pancreatitis. Clin. Biochem. 45, 1664-1668].
An FDA-approved clinical test for ischemia measures a decline in cobalt(II) binding to human albumin in blood serum. The test performed reasonably well in clinical trials [Bhagavan, N.V., Lai, E.M., Rios, P.A., Yang, J., Ortega-Lopez, A.M., Shinoda, H., Honda, S.A., Rios, C.N., Sugiyama, C.E. & Ha, C.E. (2003) Evaluation of human serum albumin cobalt binding assay for the assessment of myocardial ischemia and myocardial infarction. Clin. Chem. 49, 581-585]. The mechanism of the test is claimed to be a modification of the N-terminal binding site; yet the effect is transitory (6-24 hours) and no such ischemia-modified albumin (IMA) has yet been isolated. The first two atoms of Co(II) bind to a site involving 67His and to a nonlocalized site; only the third Co(II) may be bound to the N-terminal site [Mothes, E. & Faller, P. (2007) Evidence that the principal Co(II)-binding site in human serum albumin is not at the N-terminus: implication on the albumin cobalt binding test for detecting myocardial ischemia. Biochemistry 46, 2267-2274]. At least a partial explanation of the phenomenon seems to be a concurrent drop in albumin concentration [Zapico-Muñiz, E., Santaló-Bel, M., Mercé-Muntañola, J., Montiel, J.A., Martínez-Rubio, A. & Ordóñez-Llanos, J. (2004) Ischemia-modified albumin during skeletal muscle ischemia. Clin. Chem. 50, 1063-1065; van der Zee, P.M., Verberne, H.J., van Straalen, J.P., Sanders, G.T., Van Eck-Smit, B.L., de Winter, R.J. & Fischer, J.C. (2005) Ischemia-modified albumin measurements in symptom-limited exercise myocardial perfusion scintigraphy reflect serum albumin concentration but not myocardial ischemia. Clin. Chem. 51, 1744-1746.]. For a clinical and analytical review, see Apple, F.S. (2005) Clinical and analytical review of ischemia-modified albumin measured by the albumin cobalt binding test. Adv. Clin. Chem. 39, 1-10. Although the first clinical trials of IMA have been focused on ischemia, especially myocardial ischemia, IMA is not considered to be a specific biomarker of ischemia. However, IMA was also reported to increase in many conditions of oxidative stress that affect other organs [Uzel, M., Oray, N.C., Bayram, B., Kume, T., Girgin, M.C., Doylan, O., Saritabak, E. & Yanturali, S. (2014) New biochemical marker of seizure: ischemia-modified albumin. Am. J. Emerg. Med. Article in press. Available online 14 May 2014].
Urinary albumin excretion is an important diagnostic and prognostic marker of renal function. However, in addition to native albumin, modified forms and fragments of it can be present in the medium and thereby affect quantitation of the protein. Thus, Gudehithlu, K.P., Pegoraro, A.A., Dunea, G., Arruda, J.A. & Singh, A.K. [(2004) Degradation of albumin by the renal proximal tubule cells and the subsequent fate of its fragments. Kidney Int. 65, 2113-2122] injected (125)I-albumin into rats and found that the albumin is extensively cleaved into peptides; these are discharged both to the tubular lumen and to the renal vein. Osicka, T.M. & Comper W.D. [(2004) Characterization of immunochemically nonreactive urinary albumin. Clin. Chem. 50, 2286-2291] found a previously unrecognized form of immunochemically-unreactive albumin in urine. [see also a related editorial: Peters, T. Jr. (2004) New form of urinary albumin in early diabetes. Clin. Chem. 50, 2238-2239). The unreactive form could be seen as full-size albumin (66 kDa) upon gel exclusion chromatography or non-reducing SDS-gel electrophoresis, but disappeared into a collection of fragments when studied by reducing SDS-gel electrophoresis. Hence it appears to be a form of albumin which is heavily "nicked" by proteases but kept intact by disulfide (S-S) bonds. The average amount of unreactive albumin was ~1.5 times the amount of immunochemically-measured albumin. This finding seemed to pose a challenge for analysts of diabetic urines [Busby, D.E. & Atkins, R.C. (2005) Detection and measurement of microalbuminuria: a challenge for clinical chemistry. Med. Lab. Observer 37, 8-9]. It was estimated that >99% of the total albumin was excreted in fragmented, low-molecular mass forms (Weyer, K., Nielsen, R., Christensen, E.I. & Birn, H.J. (2012) Generation of urinary albumin fragments does not require proximal tubular uptake. Am. Soc. Nephrol. 23, 591-596]. A review on the process of albumin fragmentation and a focus on the controversial topic of immuno-unreactive, nonimmunoreactive, or immunochemically nonreactive albumin fractions and its consequences for albumin analysis can be found in Speeckaert, M.M., Speeckaert, R., Van De Voorde, L. & Delanghe, J.R. (2011) Immunochemically unreactive albumin in urine: fiction or reality? Crit. Rev. Clin. Lab. Sci. 48, 87-96. The conclusion of this article is that at present there are no hard arguments for measuring immunochemically unreactive albumin in urine. Immunoassays using polyclonal antisera for the detection of urinary albumin remain the gold standard. See also SOME PRACTICAL POINTS and the review of Doumas, B.T. & Peters, T. Jr. (1997) Serum and urine albumin: a progress report on their measurement and clinical significance. Clin. Chim. Acta 258, 3-20.
Albuminuria is associated with metabolic syndrome and diabetes. It correlates with the progression of chronic kidney disease, particularly with tubular atrophy. Abundant urinary albumin filtered through the glomerular capillaries is suggested to induce intrinsic renal toxicity, which is involved in progression of tubulointerstitial damage followed by end-stage renal disease Fatty acids bound to albumin have been reported to play important roles in the damage to renal cells caused by albumin overload through different mechanisms: (1) Arici, M., Brown, J., Williams, M., Harris, K.P., Walls, J. & Brunskill, N.J. (2002) Fatty acids carried on albumin modulate proximal tubular cell fibronectin production: a role for protein kinase C. Nephrology Dialysis Transplantation. 17, 1751-1757. (2) Arici, M., Chana, R., Lewington, A., Brown, J. & Brunskill, N.J. (2003) Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-gamma. J. Am. Soc. Nephrology 14, 17-27. (3) Ruggiero, C., Elks, C.M., Kruger, C., Cleland, E., Addison, K., Noland, R.C. & Stadler, K. (2014) Albumin-bound fatty acids but not albumin itself alter redox balance in tubular epithelial cells and induce a peroxide-mediated redox-sensitive apoptosis. Am. J. Physiol. Renal Physiol. 306, F896-906. (4). Nagai, J., Yamamoto, A., Katagiri, Y., Yumoto, R. & Takano, M.. (2014). Fatty acid-bearing albumin but not fatty acid-depleted albumin induces HIF-1 activation in human renal proximal tubular epithelial cell line HK-2. Biochem. Biophys. Res. Commun. 450(1), 476-481.
Dimeric albumin is a natural component of the circulating blood. However, albumin dimers can also be produced in vitro from monomers by chemical linkage or genetically linked with an amino acid linker. Such a product shows low vascular permeability and increased retention times in the circulation and can be used as a plasma expander. The dimer can also be used as an efficient drug carrier. For example, such a protein-drug complex has increased accumulation in tumors through the enhanced permeability and retention effect (EPR effect). For a review, see Taguchi, K., Chuang, V.T.G., Maruyama, T. & Otagiri, M. (2012) Pharmaceutical aspects of the recombinant human serum albumin dimer: structural characteristics, biological properties, and medical applications. J. Pharm. Sci. 101, 3033-3046.
The most pronounced enzymatic activities of albumin are different types of hydrolysis. Key examples are esterase-like activities involving 411Tyr or 199Lys and the thioesterase activity of 34Cys. In the first case, hydrolysis involves water and both products are released, whereas in the latter cases one of the products is set free, and the other stays covalently bound to the protein. However, the modified 34Cys can be converted back to its reduced form by another compound/enzymatic system. Among the other activities are glucuronidase, phosphatase and amidase as well as isomerase and dehydration properties. Albumin has great impact on the metabolism of, for example, eicosanoids and xenobiotics. For a review, see Kragh-Hansen, U. (2013) Molecular and practical aspects of the enzymatic properties of human serum albumin and of albumin-ligand complexes. Biochim. Biophys. Acta 1830, 5535-5544.
Albumin can stabilize different endogenous compounds. For example, it stabilizes a hydrophobic, recombinant cytokine [Hawe, A. & Friess, W. (2007) Stabilization of a hydrophobic recombinant cytokine by human serum albumin. J. Pharm. Sci. 96, 2987-2999].
The organophosphorus nerve agents sarin, soman, cyclosarin and tabun phosphylate a tyrosine residue on albumin in human blood. These adducts may offer relatively long-lived biological markers of nerve agent exposure [Williams, N.H., Harrison, J.M., Read, R.W. & Black, R.M. (2007) Phosphylated tyrosine in albumin as a biomarker of exposure to organophosphorus nerve agents. Arch.Toxicol, 81, 627-639].
Glycoprotein 60 (gp60), also called albondin, is a plasma membrane component of most continuous endothelia responsible for binding albumin and for its internalization and subsequent transcytosis. Cubilin and megalin, and complexes thereof, can internalize albumin in, for example, the proximal tubules of the kidneys. Gp18 and gp30 are found on a variety of cells, and these scavenger receptors bind conformationally-modified albumin. For a review, see Merlot, A.M., Kalinowski, D.S. & Richardson, D.R. (2014) Unraveling the mysteries of serum albumin – more than just a serum albumin. Front. Physiol. 5, Article 299. Finally, the FcRn receptor interacts with albumin in a pH-dependent manner, see above.
This receptor is reported to be a ~75kDa albumin-binding protein on the surface of endothelial cells. The resulting internalization of albumin may be important in the regulation of TGF-β responses [Siddiqui, S.S., Siddiqui, Z.K & Malik, A.B. (2004) Albumin endocytosis in endothelial cells induces TGF-beta receptor II signaling. Am. J. Physiol., Lung Cell Mol. Physiol. 286, L1016-L1026].
After physiologically relevant stress (rotation for 10 days), the plasma proteins ceruloplasmin, fibrinogen, and albumin have been shown to bind to the extracellular chaperone, clusterin. The complexes might serve as vehicles to dispose of damaged misfolded extracellular proteins in vivo via receptor-mediated endocytosis [Wyatt, A.R. & Wilson, M.R. (2010) Identification of human plasma proteins as major clients for the extracellular chaperone clusterin. J. Biol. Chem. 285, 3532-3539].
The very small amounts of albumin found in the cytosol, probably arising by leakage from cell organelles, are apparently degraded along with other soluble proteins via the "N-end rule". An arginine residue is first attached to an N-terminal aspartic or glutamic acid, leading to multiple attachments of ubiquitin and then degradation in a proteasome [Varshavsky, A. (1996) The N-end rule: functions, mysteries, uses. Proc. Natl. Acad. Sci. USA 93, 12142-12149; Graciet, E., Hu, R.G., Piatkov, K., Rhee, J.H., Schwarz, E.M. & Varshavsky, A. (2006) Aminoacyl-transferases and the N-end rule pathway of prokaryotic/eukaryotic specificity in a human pathogen. Proc. Natl. Acad. Sci. USA 103, 3078-3083]. The binding of arginine to the aspartic acid of bovine albumin by arginine-tRNA-protein transferase was first noted in 1963 (Kaji, A., Kaji, H., & Novelli, G. D. A soluble amino acid incorporating system from rat liver. Biochim. Biophys. Acta 76, 474-477) and studied extensively by Soffer, R.L. in 1973 (Post-translational modification of proteins catalyzed by aminoacyl-tRNA-protein transferases. Mol. Cell. Biochem. 2, 3-14).