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Oxidative Medicine and Cellular... 2019Alpha-macroglobulins are ancient proteins that include monomeric, dimeric, and tetrameric family members. In humans, and many other mammals, the predominant... (Review)
Review
Alpha-macroglobulins are ancient proteins that include monomeric, dimeric, and tetrameric family members. In humans, and many other mammals, the predominant alpha-macroglobulin is alpha-2-macroglobulin ( M), a tetrameric protein that is constitutively abundant in biological fluids (e.g., blood plasma, cerebral spinal fluid, synovial fluid, ocular fluid, and interstitial fluid). M is best known for its remarkable ability to inhibit a broad spectrum of proteases, but the full gamut of its activities affects diverse biological processes. For example, M can stabilise and facilitate the clearance of the Alzheimer's disease-associated amyloid beta (A) peptide. Additionally, M can influence the signalling of cytokines and growth factors including neurotrophins. The results of several studies support the idea that the functions of M are uniquely regulated by hypochlorite, an oxidant that is generated during inflammation, which induces the native M tetramer to dissociate into dimers. This review will discuss the evidence for hypochlorite-induced regulation of M and the possible implications of this in neuroinflammation and neurodegeneration.
Topics: Amyloid beta-Peptides; Animals; Humans; Hypochlorous Acid; Immune System; Neurodegenerative Diseases; Peptide Hydrolases; Pregnancy-Associated alpha 2-Macroglobulins; Protein Binding; Signal Transduction
PubMed: 31428227
DOI: 10.1155/2019/5410657 -
Journal of Thrombosis and Haemostasis :... Apr 2022Antiproteinases such as alpha-2-macroglobulin (A2M) play a role in hemostasis. A2M is highly conserved throughout evolution and is a high molecular weight... (Review)
Review
Antiproteinases such as alpha-2-macroglobulin (A2M) play a role in hemostasis. A2M is highly conserved throughout evolution and is a high molecular weight homo-tetrameric glycoprotein. A2M proteinase inhibitor activity is possible via a unique cage structure leading to proteinase entrapment without direct enzymatic activity inhibition. Following this entrapment, proteinase clearance is possible through A2M binding to the low-density lipoprotein receptor-related protein 1. A2M synthesis is regulated by pro-inflammatory cytokines and increases during several chronic or acute inflammatory diseases and varies with age. For instance, A2M plasma levels are known to be increased in patients with diabetes mellitus, nephrotic syndrome, or sepsis. Concerning hemostasis, A2M can trap many proteinases involved in coagulation and fibrinolysis. Because of its pleiotropic effects A2M can be seen as both anti- and pro-hemostatic. A2M can inhibit thrombin, factor Xa, activated protein C, plasmin, tissue-plasminogen activator, and urokinase. Through its many different functions A2M is generally put apart in the balanced regulation of hemostasis. In addition, the fact that A2M plasma levels are differently regulated during inflammatory-related diseases and that A2M can neutralize cytokines that also modify hemostasis could explain why it is difficult to link common proteins and parameters of hemostasis with the mechanisms of thrombosis in such diseases. Thus, we propose in the present review to summarize known functions of A2M, give a brief overview about diseases, and then to focus on the roles of this antiproteinase in hemostasis and thrombosis.
Topics: Cytokines; Female; Hemostasis; Humans; Pregnancy; Pregnancy-Associated alpha 2-Macroglobulins; Thrombin; Thrombosis; Transcription Factors; alpha-Macroglobulins
PubMed: 35037393
DOI: 10.1111/jth.15647 -
Methods in Enzymology 1981
Review
Topics: Binding Sites; Chemical Phenomena; Chemistry; Humans; Peptide Hydrolases; Protein Conformation; alpha-Macroglobulins
PubMed: 6176834
DOI: 10.1016/s0076-6879(81)80056-0 -
Physical Medicine and Rehabilitation... Nov 2016α-Macroglobulin (A2M) is a plasma glycoprotein best known for its ability to inhibit a broad spectrum of serine, threonine, and metalloproteases as well as inflammatory... (Review)
Review
α-Macroglobulin (A2M) is a plasma glycoprotein best known for its ability to inhibit a broad spectrum of serine, threonine, and metalloproteases as well as inflammatory cytokines by a unique bait-and-trap method. A2M has emerged as a unique potential treatment of cartilage-based pathology and inflammatory arthritides. This article describes the unique method by which A2M not only inhibits the associated inflammatory cascade but also disrupts the catabolic process of cartilage degeneration. Autologous concentrated A2M from plasma is currently in use to successfully treat various painful arthritides. Future directions will focus on recombinant variants that enhance its anti-inflammatory and disease-modifying potential.
Topics: Humans; Peptide Hydrolases; Pregnancy-Associated alpha 2-Macroglobulins; alpha-Macroglobulins
PubMed: 27788907
DOI: 10.1016/j.pmr.2016.06.008 -
Journal of Cellular Physiology Aug 2013Alpha macroglobulins are large glycoproteins which are present in the body fluids of both invertebrates and vertebrates. Alpha-2-macroglobulin (α2 M), a key member of... (Review)
Review
Alpha macroglobulins are large glycoproteins which are present in the body fluids of both invertebrates and vertebrates. Alpha-2-macroglobulin (α2 M), a key member of alpha macroglobulin superfamily, is a high-molecular weight homotetrameric glycoprotein. α2 M has many diversified and complex functions, but it is primarily known by its ability to inhibit a broad spectrum of proteases without the direct blockage of the protease active site. α2 M is also known to be involved in the regulation, transport, and a host of other functions. For example, apart from inhibiting proteinases, it regulates binding of transferrin to its surface receptor, binds defensin and myelin basic protein, etc., binds several important cytokines, including basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), interleukin-1β (IL-1β), and interleukin-6 (IL-6), and modify their biological activity. α2 M also binds a number of hormones and regulates their activity. α2 M is said to protect the body against various infections, and hence, can be used as a biomarker for the diagnosis and prognosis of a number of diseases. However, this multipurpose antiproteinse is not "fail safe" and could be damaged by reactive species generated endogenously or exogenously, leading to various pathophysiological conditions.
Topics: Animals; Binding Sites; Biomarkers; Cytokines; Humans; Protease Inhibitors; Protein Binding; Protein Conformation; alpha-Macroglobulins
PubMed: 23086799
DOI: 10.1002/jcp.24266 -
Biomeditsinskaia Khimiia 2012This review will focus on the systematization of knowledge about structure of macroglobulin signaling system, which includes macroglobulin family proteins... (Review)
Review
This review will focus on the systematization of knowledge about structure of macroglobulin signaling system, which includes macroglobulin family proteins (alpha-2-macroglobulin, alpha-2-glycoprotein, pregnancy associated plasma protein A), their receptors (LRP, grp78), ligands (proteinases, cytokines, hormones, lipids, et al.) transforming and transcriptional factors for regulation of macroglobulins synthesis. After reviewing the functions of macroglobulin signaling system, and mechanisms of their realization, we discuss the complex and significant role of this system in different physiological and pathological processes.
Topics: Animals; Biological Transport; Cytokines; Endoplasmic Reticulum Chaperone BiP; Female; Heat-Shock Proteins; Hormones; Humans; Ligands; Macroglobulins; Male; Peptide Hydrolases; Signal Transduction
PubMed: 23413684
DOI: 10.18097/pbmc20125804400 -
Experimental Gerontology Jul 2000alpha2-macroglobulin (alpha(2)M) is an abundant plasma protein similar in structure and function to a group of proteins called alpha-macroglobulins. alpha(2)M is also... (Review)
Review
alpha2-macroglobulin (alpha(2)M) is an abundant plasma protein similar in structure and function to a group of proteins called alpha-macroglobulins. alpha(2)M is also produced in the brain where it binds multiple extracellular ligands and is internalized by neurons and astrocytes. In the brain of Alzheimer's disease (AD) patients, alpha(2)M has been localized to diffuse amyloid plaques. alpha(2)M also binds soluble beta-amyloid, of which it mediates degradation. However, an excess of alpha(2)M can also have neurotoxic effects. Based on genetic evidence, is now recognized as one of the two confirmed late onset AD genes. As for the three early onset genes (the amyloid beta-protein precursor and the two presenilins) and for the other late onset gene (ApoE), DNA polymorphisms in the A2M gene associated with AD result in significantly increased accumulation of amyloid plaques in AD brains. These data support an important role for A2M in AD etiopathology.
Topics: Age of Onset; Aging; Alzheimer Disease; Humans; Polymorphism, Genetic; Structure-Activity Relationship; alpha-Macroglobulins
PubMed: 10959035
DOI: 10.1016/s0531-5565(00)00113-3 -
American Journal of Respiratory Cell... Sep 1989
Review
Topics: Growth Substances; Humans; alpha-Macroglobulins
PubMed: 2483118
DOI: 10.1165/ajrcmb/1.3.169 -
Methods in Enzymology 1976
Topics: Amino Acids; Chromatography, DEAE-Cellulose; Chromatography, Gel; Drug Stability; Fibrinolysin; Humans; Macromolecular Substances; Methods; Molecular Weight; Polyethylene Glycols; Protein Binding; Trypsin; alpha-Macroglobulins
PubMed: 64914
DOI: 10.1016/s0076-6879(76)45055-3 -
Nihon Rinsho. Japanese Journal of... Feb 1995