Editorial

3 pages, 177 KiB

Open AccessEditorial

Human Serum Albumin: From Molecular Aspects to Biotechnological Applications

by Alessandra di Masi

Int. J. Mol. Sci. 2023, 24(4), 4081; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24044081 - 17 Feb 2023

Cited by 7 | Viewed by 1746

Human serum albumin (HSA), the most abundant protein in plasma, is a monomeric multidomain macromolecule that represents the main determinant of plasma oncotic pressure and the principal modulator of fluid distribution between body compartments [...] Full article

(This article belongs to the Special Issue Human Serum Albumin: From Molecular Aspects to Biotechnological Applications)

Research

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15 pages, 1813 KiB

Open AccessArticle

Association between Albumin Alterations and Renal Function in Patients with Type 2 Diabetes Mellitus

by Marta Nugnes, Maurizio Baldassarre, Danilo Ribichini, Daniele Tedesco, Irene Capelli, Daniele Vetrano, Francesca Marchignoli, Lucia Brodosi, Enrico Pompili, Maria Letizia Petroni, Gaetano La Manna, Giulio Marchesini, Marina Naldi and Manuela Bartolini

Int. J. Mol. Sci. 2024, 25(6), 3168; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063168 - 09 Mar 2024

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Abstract

Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). The aim of this study was to investigate whether albumin structural alterations correlate with DKD severity and evaluate whether native and reduced albumin [...] Read more.

Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). The aim of this study was to investigate whether albumin structural alterations correlate with DKD severity and evaluate whether native and reduced albumin concentrations could complement the diagnosis of DKD. To this end, one hundred and seventeen T2DM patients without (n = 42) and with (n = 75) DKD (DKD I-III upon KDIGO classification) were evaluated; the total albumin concentration (tHA) was quantified by a bromocresol green assay, while structural alterations were profiled via liquid chromatography–high-resolution mass spectrometry (LC-HRMS). The concentrations of native albumin (eHA, effective albumin) and reduced albumin (rHA) were subsequently assessed. The HRMS analyses revealed a reduced relative amount of native albumin in DKD patients along with an increased abundance of altered forms, especially those bearing oxidative modifications. Accordingly, both eHA and rHA values varied during the stages of progressive renal failure, and these alterations were dose-dependently correlated with renal dysfunction. A ROC curve analysis revealed a significantly greater sensitivity and specificity of eHA and rHA than of tHA for diagnosing DKD. Importantly, according to the multivariate logistic regression analysis, the eHA was identified as an independent predictor of DKD. Full article

(This article belongs to the Special Issue Human Serum Albumin: From Molecular Aspects to Biotechnological Applications)

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13 pages, 2578 KiB

Open AccessArticle

Structural Analysis of Human Serum Albumin in Complex with the Fibrate Drug Gemfibrozil

by Stefano Liberi, Sara Linciano, Giulia Moro, Luca De Toni, Laura Cendron and Alessandro Angelini

Int. J. Mol. Sci. 2022, 23(3), 1769; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031769 - 04 Feb 2022

Cited by 8 | Viewed by 2902

Abstract

Gemfibrozil (GEM) is an orally administered lipid-regulating fibrate derivative drug sold under the brand name Lopid^®, among others. Since its approval in the early 80s, GEM has been largely applied to treat hypertriglyceridemia and other disorders of lipid metabolism. Though generally [...] Read more.

Gemfibrozil (GEM) is an orally administered lipid-regulating fibrate derivative drug sold under the brand name Lopid^®, among others. Since its approval in the early 80s, GEM has been largely applied to treat hypertriglyceridemia and other disorders of lipid metabolism. Though generally well tolerated, GEM can alter the distribution and the free, active concentration of some co-administered drugs, leading to adverse effects. Most of them appear to be related to the ability of GEM to bind with high affinity human serum albumin (HSA), the major drug-carrier protein in blood plasma. Here, we report the crystal structure of HSA in complex with GEM. Two binding sites have been identified, namely Sudlow’s binding sites I (FA7) and II (FA3–FA4). A comparison of the crystal structure of HSA in complex with GEM with those of other previously described HSA–drug complexes enabled us to appreciate the analogies and differences in their respective binding modes. The elucidation of the molecular interaction between GEM and HSA might offer the basis for the development of novel GEM derivatives that can be safely and synergistically co-administered with other drugs, enabling augmented therapeutic efficacies. Full article

(This article belongs to the Special Issue Human Serum Albumin: From Molecular Aspects to Biotechnological Applications)

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15 pages, 2939 KiB

Open AccessArticle

Development of Cobalt-Binding Peptide Chelate from Human Serum Albumin: Cobalt-Binding Properties and Stability

by Yeonje Cho, Armin Mirzapour-Kouhdasht, Hyosuk Yun, Jeong Hoon Park, Hye Jung Min and Chul Won Lee

Int. J. Mol. Sci. 2022, 23(2), 719; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020719 - 10 Jan 2022

Cited by 3 | Viewed by 1908

Abstract

Radioactive isotopes are used as drugs or contrast agents in the medical field after being conjugated with chelates such as DOTA, NOTA, DTPA, TETA, CyDTA, TRITA, and DPDP. The N-terminal sequence of human serum albumin (HSA) is known as a metal binding site, [...] Read more.

Radioactive isotopes are used as drugs or contrast agents in the medical field after being conjugated with chelates such as DOTA, NOTA, DTPA, TETA, CyDTA, TRITA, and DPDP. The N-terminal sequence of human serum albumin (HSA) is known as a metal binding site, such as for Co²⁺, Cu²⁺, and Ni²⁺. For this study, we designed and synthesized wAlb12 peptide from the N-terminal region of HSA, which can bind to cobalt, to develop a peptide-based chelate. The wAlb12 with a random coil structure tightly binds to the Co(II) ion. Moreover, the binding property of wAlb12 toward Co(II) was confirmed using various spectroscopic experiments. To identify the binding site of wAlb12, the analogs were synthesized by alanine scanning mutagenesis. Among them, H3A and Ac-wAlb12 did not bind to Co(II). The analysis of the binding regions confirmed that the His3 and α-amino group of the N-terminal region are important for Co(II) binding. The wAlb12 bound to Co(II) with K_d of 75 μM determined by isothermal titration calorimetry when analyzed by a single-site binding model. For the use of wAlb12 as a chelate in humans, its cytotoxicity and stability were investigated. Trypsin stability showed that the wAlb12 − Co(II) complex was more stable than wAlb12 alone. Furthermore, the cell viability analysis showed wAlb12 and wAlb12 + Co(II) to be non-toxic to the Raw 264.7 and HEK 293T cell lines. Therefore, a hot radioactive isotope such as cobalt-57 will have the same effect as a stable isotope cobalt. Accordingly, we expect wAlb12 to be used as a peptide chelate that binds with radioactive isotopes. Full article

(This article belongs to the Special Issue Human Serum Albumin: From Molecular Aspects to Biotechnological Applications)

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13 pages, 6673 KiB

Open AccessArticle

Functionalization of Human Serum Albumin by Tyrosine Click

by Satsuki Obara, Keita Nakane, Chizu Fujimura, Shusuke Tomoshige, Minoru Ishikawa and Shinichi Sato

Int. J. Mol. Sci. 2021, 22(16), 8676; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168676 - 12 Aug 2021

Cited by 4 | Viewed by 2507

Abstract

Human serum albumin (HSA) is a promising drug delivery carrier. Although covalent modification of Cys34 is a well-established method, it is desirable to develop a novel covalent modification method that targets residues other than cysteine to introduce multiple functions into a single HSA [...] Read more.

Human serum albumin (HSA) is a promising drug delivery carrier. Although covalent modification of Cys34 is a well-established method, it is desirable to develop a novel covalent modification method that targets residues other than cysteine to introduce multiple functions into a single HSA molecule. We developed a tyrosine-selective modification of HSA. Three tyrosine selective modification methods, hemin-catalyzed, horseradish peroxidase (HRP)-catalyzed, and laccase-catalyzed reactions were performed, and the modification efficiencies and modification sites of the modified HSAs obtained by these methods were evaluated and compared. We found that the laccase-catalyzed method could efficiently modify the tyrosine residue of HSA under mild reaction conditions without inducing oxidative side reactions. An average of 2.2 molecules of functional groups could be introduced to a single molecule of HSA by the laccase method. Binding site analysis using mass spectrometry suggested Y84, Y138, and Y401 as the main modification sites. Furthermore, we evaluated binding to ibuprofen and found that, unlike the conventional lysine residue modification, the inhibition of drug binding was minimal. These results suggest that tyrosine-residue selective chemical modification is a promising method for covalent drug attachment to HSA. Full article

(This article belongs to the Special Issue Human Serum Albumin: From Molecular Aspects to Biotechnological Applications)

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Review

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19 pages, 402 KiB

Open AccessReview

Variations in the Human Serum Albumin Gene: Molecular and Functional Aspects

by Gianluca Caridi, Francesca Lugani, Andrea Angeletti, Monica Campagnoli, Monica Galliano and Lorenzo Minchiotti

Int. J. Mol. Sci. 2022, 23(3), 1159; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031159 - 21 Jan 2022

Cited by 8 | Viewed by 2889

Abstract

The human albumin gene, the most abundant serum protein, is located in the long arm of chromosome 4, near the centromere, position 4q11–3. It is divided by 14 intervening introns into 15 exons, the last of which is untranslated. To date, 74 nucleotide [...] Read more.

The human albumin gene, the most abundant serum protein, is located in the long arm of chromosome 4, near the centromere, position 4q11–3. It is divided by 14 intervening introns into 15 exons, the last of which is untranslated. To date, 74 nucleotide substitutions (mainly missense) have been reported, determining the circulating variants of albumin or pre-albumin. In a heterozygous state, this condition is known as alloalbuminaemia or bisalbuminaemia (OMIM # 103600). The genetic variants are not associated with disease, neither in the heterozygous nor in the homozygous form. Only the variants resulting in familial dysalbuminaemic hyperthyroxinaemia and hypertriiodothyroninaemia are of clinical relevance because affected individuals are at risk of inappropriate treatment or may have adverse drug effects. In 28 other cases, the pathogenic variants (mainly affecting splicing, nonsense, and deletions), mostly in the homozygous form, cause a premature stop in the synthesis of the protein and lead to the condition known as congenital analbuminaemia. In this review, we will summarize the current knowledge of genetic and molecular aspects, functional consequences and potential therapeutic uses of the variants. We will also discuss the molecular defects resulting in congenital analbuminaemia, as well as the biochemical and clinical features of this rare condition Full article

(This article belongs to the Special Issue Human Serum Albumin: From Molecular Aspects to Biotechnological Applications)

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23 pages, 1840 KiB

Open AccessReview

Serum Albumin: A Multifaced Enzyme

by Giovanna De Simone, Alessandra di Masi and Paolo Ascenzi

Int. J. Mol. Sci. 2021, 22(18), 10086; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810086 - 18 Sep 2021

Cited by 83 | Viewed by 6222

Abstract

Human serum albumin (HSA) is the most abundant protein in plasma, contributing actively to oncotic pressure maintenance and fluid distribution between body compartments. HSA acts as the main carrier of fatty acids, recognizes metal ions, affects pharmacokinetics of many drugs, provides the metabolic [...] Read more.

Human serum albumin (HSA) is the most abundant protein in plasma, contributing actively to oncotic pressure maintenance and fluid distribution between body compartments. HSA acts as the main carrier of fatty acids, recognizes metal ions, affects pharmacokinetics of many drugs, provides the metabolic modification of some ligands, renders potential toxins harmless, accounts for most of the anti-oxidant capacity of human plasma, and displays esterase, enolase, glucuronidase, and peroxidase (pseudo)-enzymatic activities. HSA-based catalysis is physiologically relevant, affecting the metabolism of endogenous and exogenous compounds including proteins, lipids, cholesterol, reactive oxygen species (ROS), and drugs. Catalytic properties of HSA are modulated by allosteric effectors, competitive inhibitors, chemical modifications, pathological conditions, and aging. HSA displays anti-oxidant properties and is critical for plasma detoxification from toxic agents and for pro-drugs activation. The enzymatic properties of HSA can be also exploited by chemical industries as a scaffold to produce libraries of catalysts with improved proficiency and stereoselectivity for water decontamination from poisonous agents and environmental contaminants, in the so called “green chemistry” field. Here, an overview of the intrinsic and metal dependent (pseudo-)enzymatic properties of HSA is reported to highlight the roles played by this multifaced protein. Full article

(This article belongs to the Special Issue Human Serum Albumin: From Molecular Aspects to Biotechnological Applications)

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16 pages, 1136 KiB

Open AccessReview

Structural and Biochemical Features of Human Serum Albumin Essential for Eukaryotic Cell Culture

by Vibhor Mishra and Richard J. Heath

Int. J. Mol. Sci. 2021, 22(16), 8411; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168411 - 05 Aug 2021

Cited by 74 | Viewed by 8622

Abstract

Serum albumin physically interacts with fatty acids, small molecules, metal ions, and several other proteins. Binding with a plethora of bioactive substances makes it a critical transport molecule. Albumin also scavenges the reactive oxygen species that are harmful to cell survival. These properties [...] Read more.

Serum albumin physically interacts with fatty acids, small molecules, metal ions, and several other proteins. Binding with a plethora of bioactive substances makes it a critical transport molecule. Albumin also scavenges the reactive oxygen species that are harmful to cell survival. These properties make albumin an excellent choice to promote cell growth and maintain a variety of eukaryotic cells under in vitro culture environment. Furthermore, purified recombinant human serum albumin is mostly free from impurities and modifications, providing a perfect choice as an additive in cell and tissue culture media while avoiding any regulatory constraints. This review discusses key features of human serum albumin implicated in cell growth and survival under in vitro conditions. Full article

(This article belongs to the Special Issue Human Serum Albumin: From Molecular Aspects to Biotechnological Applications)

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