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At least 19 recordsLinked to original sources
PubMed1986

Cell surface molecule associated with lymphocyte homing is a ubiquitinated branched-chain glycoprotein.

Partial amino acid sequence analysis of a purified lymphocyte homing receptor demonstrates the presence of two amino termini, one of which corresponds precisely to the amino terminus of ubiquitin. This observation extends the province of this conserved polypeptide to the cell surface and leads to a proposed model of the receptor complex as a core polypeptide modified by glycosylation and ubiquitination. Independent antibodies to ubiquitin serve to identify additional cell surface species, an indication that ubiquitination of cell surface proteins may be more general. It is proposed that functional binding of lymphocytes to lymph node high endothelial venules might involve the ubiquitinated region of the receptor; if true, cell surface ubiquitin could play a more general role in cell-cell interaction and adhesion.

Amino Acid Sequence↗
PubMed2026

Molecular mechanism of HUWE1-HAPSTR1-USP7-mediated ubiquitin chain amplification on nuclear proteins.

Rapid protein turnover is essential for cellular stress adaptation. HUWE1 (HECT, UBA, and WWE domain containing 1), a large HECT-type E3 ligase, regulates many short-lived stress-responsive proteins, yet the mechanisms underlying its substrate selectivity remain unclear. Here, we reveal that HUWE1 functions as a ubiquitin chain amplifier that captures pre-ubiquitinated substrates and amplifies the degradation signal by assembling long ubiquitin chains containing K11-K48 branch points, a process regulated by its partners HUWE1-associated protein stress response 1 (HAPSTR1) and USP7 (ubiquitin-specific-processing protease 7). Structural and biochemical analyses show that HAPSTR1 engages HUWE1's ubiquitin-binding motifs to drive nuclear import and modulate substrate recruitment. A cryo-EM structure of the HUWE1-USP7 complex reveals a bidirectional regulatory mechanism: HUWE1 activates USP7's catalytic activity, while USP7 modulates HUWE1 conformational states. Global proteomic analyses demonstrate that this axis drives extensive remodeling of the short-lived nuclear proteome. These findings establish the HUWE1-HAPSTR1-USP7 complex as a key ubiquitin code modifier, providing a molecular rationale for HUWE1 dysregulation in neurodevelopmental disorders and cancer.

Ubiquitin-Specific Peptidase 7↗
PubMed2003

A novel type of deubiquitinating enzyme.

A previous report from this laboratory described two novel proteins that have sequence similarity to A20, a negative regulator of NF-kappaB (Evans, P. C., Taylor, E. R., Coadwell, J., Heyninck, K., Beyaert, R., and Kilshaw, P. J. (2001) Biochem. J. 357, 617-623). One of these molecules, cellular zinc finger anti-NF-kappaB (Cezanne), a 100-kDa cytoplasmic protein, also suppressed NF-kappaB. Here we demonstrate that Cezanne is a novel deubiquitinating enzyme, distinct from the two known families of deubiquitinases, Types I and II. We show that Cezanne contains an N-terminal catalytic domain that belongs to the recently discovered ovarian tumor protein (OTU) superfamily, a group of proteins displaying structural similarity to cysteine proteases but having no previously described function. Recombinant Cezanne cleaved ubiquitin monomers from linear or branched synthetic ubiquitin chains and from ubiquitinated proteins. Mutation of a conserved cysteine residue in the catalytic site of the proteolytic domain caused Cezanne to co-precipitate polyubiquitinated cellular proteins. We also provide evidence for an additional ubiquitin binding site in the C-terminal part of the molecule. Our data provide the first demonstration of functional activity among OTU proteins.

Amino Acid Sequence↗
PubMed1989

A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein.

The ubiquitin-dependent degradation of a test protein beta-galactosidase (beta gal) is preceded by ubiquitination of beta gal. The many (from 1 to more than 20) ubiquitin moieties attached to a molecule of beta gal occur as an ordered chain of branched ubiquitin-ubiquitin conjugates in which the carboxyl-terminal Gly76 of one ubiquitin is jointed to the internal Lys48 of an adjacent ubiquitin. This multiubiquitin chain is linked to one of two specific Lys residues in beta gal. These same Lys residues have been identified by molecular genetic analysis as components of the aminoterminal degradation signal in beta gal. The experiments with ubiquitin mutated at its Lys48 residue indicate that the multiubiquitin chain in a targeted protein is essential for the degradation of the protein.

DNA Mutational Analysis↗
PubMed1997

The search for the uremic toxin: the case for metabolic acidosis.

Much effort has been expended on determining which compound, hormone or metabolic condition causes the uremic syndrome. Byproducts of protein metabolism that can cause uremic symptoms, including loss of lean body mass, have been a focus of research but specific toxins have been difficult to identify. Evidence is provided that implicates metabolic acidosis as the prime signal initiating muscle wasting in uremia since it activates branched-chain ketoacid dehydrogenase and the ubiquitin proteasome pathway. These responses degrade the essential branched chain amino acids and protein in muscle, leading to loss of muscle mass. Correction of the metabolic acidosis with sodium bicarbonate supplements has significant therapeutic implications for uremic patients with even mild degrees of metabolic acidosis.

Acidosis↗
PubMed1997

Purification and characterization of UBP6, a new ubiquitin-specific protease in Saccharomyces cerevisiae.

Ubiquitin-specific protease-6 (UBP6) in Saccharomyces cerevisiae was expressed in Escherichia coli and purified from the cells using 125I-labeled ubiquitin-alphaNH-MHISPPEPESEEEEEHYC as a model substrate. The purified UBP6 behaved as a 58-kDa under both nondenaturing and denaturing conditions, indicating that the enzyme comprises a single polypeptide. It was maximally active at pH levels between 8.5 and 9, but showed little or no activity at pH below 7 and above 9.5. As with other UBPs, its activity was strongly inhibited by sulfhydryl-blocking reagents, such as N-ethylmaleimide, and by ubiquitin-aldehyde. In addition to the model substrate, UBP6 hydrolyzed ubiquitin-alphaNH-protein extensions, such as the ubiquitin-alphaNH-carboxyl extension protein of 80 amino acids and ubiquitin-alphaNH-dihydrofolate reductase, but not poly-His-tagged diubiquitin. It was also capable of releasing free ubiquitin from branched polyubiquitin chains that are ligated to proteins through epsilonNH-isopeptide bonds, although to a limited extent. These results suggest that UBP6 may play an important role in the generation of free ubiquitins and certain ribosomal proteins from ubiquitin-ribosomal fusion proteins as well as in deubiquitination of certain polyubiquitinated proteins targeted for degradation by the 26S proteasomes.

Amino Acid Sequence↗
PubMed1997

Purification and characterization of a new ubiquitin C-terminal hydrolase (UCH-1) with isopeptidase activity from chick skeletal muscle.

We have previously shown that chick muscle extracts contain at least 10 different ubiquitin C-terminal hydrolases (UCHs). In the present studies, one of the enzymes, called UCH-1 was partially purified by conventional chromatographic procedures using (125)I-labeled ubiquitin-alphaNH-MHISPPEPESEEEEEHYC as a substrate. The purified enzyme behaved as a 35-kDa protein under both denaturing and nondenaturing conditions, suggesting that it consisted of a single polypeptide chain. It was maximally active at pHs between 8 and 9, but showed little or no activity at pH below 6 and above 11. Like other UCHs, its activity was strongly inhibited by sulfhydryl blocking reagents, such as iodoacetamide, and by ubiquitin-aldehyde. In addition to Ub-PESTc, UCH-1 hydrolyzed ubiquitin-alphaNH-protein extensions, including ubiquitin-alphaNH-carboxyl extension protein of 80 amino acids, ubiquitin-alphaNH-dihydrofolate reductase, and poly-His-tagged di-ubiquitin. This enzyme was also capable of generating free ubiquitin from mono-ubiquitin-epsilonNH-protein conjugates and from branched poly-ubiquitin chains that are ligated to proteins through epsilon NH-isopeptide bonds. These results suggest that UCH-1 may play an important role in the generation of free ubiquitin from ubiquitin-ribosomal protein fusions and linear poly-ubiquitin, as well as in recycling of Ub molecules after degradation of poly-ubiquitinated protein conjugates by the 26S proteasome.

Amino Acid Sequence↗
PubMed1997

Molecular cloning of a novel ubiquitin-specific protease, UBP41, with isopeptidase activity in chick skeletal muscle.

A cDNA encoding a new ubiquitin-specific protease, UBP41, in chick skeletal muscle was cloned using an Escherichia coli-based in vivo screening method. Nucleotide sequence analysis of the cDNA containing an open reading frame of 1,071 base pairs revealed that the protease consists of 357 residues with a calculated molecular mass of 40,847 Da, and is related to members of the UBP family containing highly conserved Cys and His domains. Chick UBP41 was expressed in E. coli and purified from the cells to apparent homogeneity, using 125I-labeled ubiquitin-alphaNH-MHISPPEPESEEEEEHYC as a substrate. The purified enzyme behaved as an approximately 43-kDa protein under both denaturing and nondenaturing conditions, suggesting that it consists of a single polypeptide chain. Like other deubiquitinating enzymes, it was sensitive to inhibition by ubiquitin-aldehyde and sulfhydryl blocking agents, such as N-ethylmaleimide. The UBP41 protease cleaved at the C terminus of the ubiquitin moiety in natural and engineered fusions irrespective of their sizes; thus, it is active against ubiquitin-beta-galactosidase as well as ubiquitin C-terminal extension protein of 80 amino acids. UBP41 also released free ubiquitin from poly-His-tagged di-ubiquitin. Moreover, it converted poly-ubiquitinated lysozyme conjugates to mono-ubiquitinated forms of about 24 kDa, although the latter molecules were not further degraded to free ubiquitin and lysozyme. These results suggest that UBP41 may play an important role in the recycling of ubiquitin by hydrolysis of branched poly-ubiquitin chains generated by the action of 26 S proteasome on poly-ubiquitinated protein substrates, as well as in the production of free ubiquitin from linear poly-ubiquitin chains and of certain ribosomal proteins from ubiquitin fusion proteins.

Amino Acid Sequence↗
PubMed1989

The degradation signal in a short-lived protein.

Our previous work has shown that the amino-terminal residue of a short-lived protein is a distinct component of the protein's degradation signal. To define the complete signal, otherwise identical dihydrofolate reductase test proteins bearing different extensions and either a "stabilizing" or a "destabilizing" amino-terminal residue were expressed in the yeast S. cerevisiae and their in vivo half-lives compared. The amino-terminal degradation signal is shown to comprise two distinct determinants. One, discovered previously, is the protein's amino-terminal residue. The second determinant, identified in the present work, is a specific lysine residue whose function in the degradation signal is not dependent on the unique amino acid sequences in the vicinity of the residue. The mechanistic significance of the second determinant is illuminated by the finding that in a targeted, short-lived protein, a chain of branched ubiquitin-ubiquitin conjugates is confined to a lysine residue that has been identified in the present work as the second determinant of the degradation signal.

Amino Acid Sequence↗
PubMed2004

Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity.

Ubiquitination regulates the stability and/or activity of numerous cellular proteins. The corollary is that de-ubiquitinating enzymes, which 'trim' polyubiquitin chains from specific substrate proteins, play key roles in controlling fundamental cellular activities. Ubiquitin is essential at several stages during the activation of NF-kappaB (nuclear factor kappaB), a central co-ordinator of inflammation and other immune processes. Ubiquitination is known to cause degradation of the inhibitory molecule IkappaBalpha (inhibitor of kappaB). In addition, activation of TRAF (tumour-necrosis-factor-receptor-associated factor) and IKKgamma (IkappaB kinase gamma)/NEMO (NF-kappaB essential modifier) signal adaptors relies on their modification with 'nonclassical' forms of polyubiquitin chains. Ubiquitin also plays a key role in determining cell fate by modulating the stability of numerous pro-apoptotic or anti-apoptotic proteins. The zinc-finger protein A20 has dual functions in inhibiting NF-kappaB activation and suppressing apoptosis. The molecular mechanisms of these anti-inflammatory and cytoprotective effects are unknown. Here we demonstrate that A20 is a de-ubiquitinating enzyme. It contains an N-terminal catalytic domain that belongs to the ovarian-tumour superfamily of cysteine proteases. A20 cleaved ubiquitin monomers from branched polyubiquitin chains linked through Lys48 or Lys63 and bound covalently to a thiol-group-reactive, ubiquitin-derived probe. Mutation of a conserved cysteine residue in the catalytic site (Cys103) abolished these activities. A20 did not have a global effect on ubiquitinated cellular proteins, which indicates that its activity is target-specific. The biological significance of the catalytic domain is unknown.

Animals↗
PubMed1990

Ubiquitin-mediated degradation of histone H3 does not require the substrate-binding ubiquitin protein ligase, E3, or attachment of polyubiquitin chains.

Radioiodinated histone H3 was incubated with ubiquitin, the ubiquitin-activating enzyme E1, and one of three ubiquitin carrier proteins, reticulocyte E2(20K) or E2(32K) or the yeast RAD6 product. Although the resulting ubiquitin-histone conjugates were synthesized in the absence of the substrate-binding protein E3, they were nevertheless degraded by purified rabbit reticulocyte 26 S protease. In contrast, unmodified histone H3 remained intact upon challenge with the 26 S ubiquitin/ATP-dependent enzyme. Conjugates produced by the RAD6 protein were better proteolytic substrates than those formed by reticulocyte E2 unless ubiquitin molecules with altered lysines were used for conjugate synthesis. Substitution of methylated ubiquitin or ubiquitin molecules in which lysine 48 was converted to arginine by site-directed mutation produced histone conjugates that were degraded at slow but measurable rates. Since methylated ubiquitin molecules are incapable of forming branched polyubiquitin chains, these results demonstrate that neither ubiquitin "trees" nor the substrate binding factor E3 is absolutely required for ubiquitin-dependent degradation of histone H3 in vitro.

Animals↗
PubMed2005

Using deubiquitylating enzymes as research tools.

Ubiquitin is synthesized in eukaryotes as a linear fusion with a normal peptide bond either to itself or to one of two ribosomal proteins and, in the latter case, enhances the yield of these ribosomal proteins and/or their incorporation into the ribosome. Such fusions are cleaved rapidly by a variety of deubiquitylating enzymes. Expression of heterologous proteins as linear ubiquitin fusions has been found to significantly increase the yield of unstable or poorly expressed proteins in either bacterial or eukaryotic hosts. If expressed in bacterial cells, the fusion is not cleaved due to the absence of deubiquitylating activity and can be purified intact. We have developed an efficient expression system, utilizing the ubiquitin fusion technique and a robust deubiquitylating enzyme, which allows convenient high yield and easy purification of authentic proteins. An affinity purification tag on both the ubiquitin fusion and the deubiquitylating enzyme allows their easy purification and the easy removal of unwanted components after cleavage, leaving the desired protein as the only soluble product. Ubiquitin is also conjugated to epsilon amino groups in lysine side chains of target proteins to form a so-called isopeptide linkage. Either a single ubiquitin can be conjugated or other lysines within ubiquitin can be acceptors for further conjugation, leading to formation of a branched, isopeptide-linked ubiquitin chain. Removal of these ubiquitin moieties or chains in vitro would be a valuable tool in the ubiquitinologists tool kit to simplify downstream studies on ubiquitylated targets. The robust deubiquitylating enzyme described earlier is also very useful for this task.

Amino Acid Sequence↗
PubMed2003

Markers of inflammation, proteolysis, and apoptosis in ESRD.

BACKGROUND: Hemodialysis (HD) is associated with protein catabolism and augmented apoptosis. Although the effect of metabolic acidosis and inflammatory cytokines on activation of the ubiquitin-proteasome pathway and branched-chain keto acid dehydrogenase (BCKAD) is well known, the effect of HD on these pathways remains unexplored. METHODS: Twelve patients with end-stage renal disease were studied before and during HD. Eight controls also were studied. Plasma levels of complement components and cytokines, interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured. Messenger RNA (mRNA) levels of caspase-3, a mediator of apoptosis; ubiquitin, a marker of proteolysis; and BCKAD-E2, an enzyme regulating branched-chain amino acid oxidation, were estimated in skeletal muscle biopsy specimens by means of reverse-transcriptase polymerase chain reaction. Annexin-V expression was quantified by DNA array. Before the study, participants were placed on a 1.2-g/kg/d protein diet, and metabolic acidosis was corrected. RESULTS: During HD, plasma IL-6 levels increased from 7.54 +/- 2.24 to 27.86 +/- 4.94 pg/dL (P < 0.001). Complement component, IL-1, and TNF-alpha levels did not change significantly during HD. mRNA levels of caspase-3 (0.50 +/- 0.01 versus 0.81 +/- 0.04), annexin-V (0.94 +/- 0.06 versus 1.48 +/- 0.05; P < 0.001), ubiquitin (1.10 +/- 0.03 versus 1.44 +/- 0.03), and BCKAD-E2 (0.47 +/- 0.01 versus 0.81 +/- 0.04) increased in muscle during HD compared with pre-HD values (P < 0.001). mRNA levels of ubiquitin (0.62 +/- 0.03) and BCKAD-E2 (0.58 +/- 0.02) were greater in controls than pre-HD values (P < 0.05). There were significant positive correlations between plasma IL-6 levels and expression of caspase-3, ubiquitin, and BCKAD-E2 genes. CONCLUSION: HD causes activation of cytokines, which may mediate the increase in gene expression of caspase-3, ubiquitin, and BCKAD-E2 in skeletal muscles.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMedDate not supplied

Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure.

Metabolic acidosis, a common condition in patients with renal failure, may be linked to protein-energy malnutrition (PEM) and inflammation, together also known as malnutrition-inflammation complex syndrome (MICS). Methods of serum bicarbonate measurement may misrepresent the true bicarbonate level, since the total serum carbon dioxide measurement usually overestimates the serum bicarbonate concentration. Moreover, the air transportation of blood samples to distant laboratories may lead to erroneous readings. In patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD), a significant number of endocrine, musculoskeletal, and metabolic abnormalities are believed to result from acidemia. Metabolic acidosis may be related to PEM and MICS due to an increased protein catabolism, decreased protein synthesis, endocrine abnormalities including insulin resistance, decreased serum leptin level, and inflammation among individuals with renal failure. Evidence suggests that the catabolic effects of metabolic acidosis may result from an increased activity of the adenosine triphosphate (ATP)-dependent ubiquitin-proteasome and branched-chain keto acid dehydrogenase. In contrast to the metabolic studies, many epidemiologic studies in maintenance dialysis patients have indicated a paradoxically inverse association between mildly decreased serum bicarbonate and improved markers of protein-energy nutritional state. Hence metabolic acidosis may be considered as yet another element of the reverse epidemiology in ESRD patients. Interventional studies have yielded inconsistent results in CKD and ESRD patients, although in peritoneal dialysis patients, mitigating acidemia appears to more consistently improve nutritional status and reduce hospitalizations. Large-scale, prospective randomized interventional studies are needed to ascertain the potential benefits of correcting acidemia in malnourished and/or inflamed CKD and maintenance hemodialysis patients. Until then, all attempts should be made to adhere to the National Kidney Foundation Kidney Disease and Dialysis Outcome Quality Initiative guidelines to maintain a serum bicarbonate level in ESRD patients of at least 22 mEq/L.

Acidosis↗
PubMed2004

The ubiquitin system: from basic mechanisms to the patient bed.

In the ubiquitin system, a target substrate is modified by ubiquitin or a ubiquitin-like protein. This modification remodels the surface of the target proteins, affecting, among other properties, their stability, interactions with other proteins, activity, and subcellular localization. At least 10 different modifiers have been described in mammalian cells and conjugation of each modifier to its target may result in a different biological effect. In many cases proteins are modified by multiple moieties of ubiquitin that generate a branched polyubiquitin chain. For most proteins, this modification leads to their degradation by the 26S proteasome. Yet, dependent on the character of the internal linkage between the ubiquitin moieties, it can also lead to activation of transcriptional regulators. Modification by a single moiety of ubiquitin can target proteins for degradation in the lysosome/vacuole. Conjugation of ubiquitin or ubiquitin-like proteins can serve a variety of non-proteolytic functions, such as activation of enzymes, modulation of membrane dynamics, or routing of the tagged proteins to their sub-cellular destination. Ubiquitination of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that targets, in a specific manner, thousands of cellular proteins. It is carried out by a modular cascade of enzymes with high specificity towards defined structural motifs in the target proteins. It has emerged as a critically important post-translational modification that plays major roles in regulating a broad array of basic cellular processes, such as cell division, differentiation, signal transduction, trafficking, and quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of many diseases, certain malignancies, neurodegenerative disorders and pathologies of the inflammatory and immune response among them. Understanding of the underlying mechanisms involved is important for the development of novel, mechanism-based drugs.

Cystic Fibrosis↗
PubMed2003

Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase.

The breast and ovarian cancer suppressor BRCA1 acquires significant ubiquitin ligase activity when bound to BARD1 as a RING heterodimer. Although the activity may well be important for the role of BRCA1 as a tumor suppressor, the biochemical consequence of the activity is not yet known. Here we report that BRCA1-BARD1 catalyzes Lys-6-linked polyubiquitin chain formation. K6R mutation of ubiquitin dramatically reduces the polyubiquitin products mediated by BRCA1-BARD1 in vitro. BRCA1-BARD1 preferentially utilizes ubiquitin with a single Lys residue at Lys-6 or Lys-29 to mediate autoubiquitination of BRCA1 in vivo. Furthermore, mass spectrometry analysis identified the Lys-6-linked branched ubiquitin fragment from the polyubiquitin chain produced by BRCA1-BARD1 using wild type ubiquitin. The BRCA1-BARD1-mediated Lys-6-linked polyubiquitin chains are deubiquitinated by 26 S proteasome in vitro, whereas autoubiquitinated CUL1 through Lys-48-linked polyubiquitin chains is degraded. Proteasome inhibitors do not alter the steady state level of the autoubiquitinated BRCA1 in vivo. Hence, the results indicate that BRCA1-BARD1 mediates novel polyubiquitin chains that may be distinctly edited by 26 S proteasome from conventional Lys-48-linked polyubiquitin chains.

Amino Acid Sequence↗
PubMed1995

Metabolism of the polyubiquitin degradation signal: structure, mechanism, and role of isopeptidase T.

A necessary step in ubiquitin-dependent proteolysis is the addition of a polyubiquitin chain to the target protein. This ubiquitinated protein is degraded by a multisubunit complex known as the 26S proteasome. The polyubiquitin chain is probably not released until a late stage in the proteolysis by the proteasome. It is subsequently disassembled to yield functional ubiquitin monomers. Here we present evidence that a 93 kDa protein, isopeptidase T, has the properties expected for the enzyme which disassembles these branched polyubiquitin chains. Protein and cDNA sequencing revealed that isopeptidase T is a member of the ubiquitin specific protease family (UBP). Isopeptidase T disassembles branched polyubiquitin chains (linked by the G76-K48 isopeptide bond) by a sequential exo mechanism, starting at the proximal end of the chain (the proximal ubiquitin contains a free carboxyl-terminus). Isopeptidase T prefers to disassemble chains in which there is an intact and unblocked RGG sequence at the C-terminus of the proximal subunit. Rates of disassembly are reduced when G76 of the proximal ubiquitin is modified, for example, by ligation to substrate protein, by esterification, by replacement of the proximal glycine with alanine (G76A), or by truncation. Linear proubiquitin is only a poor substrate. Observed rates and specificity are consistent with isopeptidase T playing a major role in disassembly of polyubiquitin chains. The high discrimination against chains that are blocked or modified at the proximal end indicates that the enzyme acts after release of the chains from conjugated proteins or degradation intermediates. Thus, the proteolytic degradation signal is not disassembled by isopeptidase T before the ubiquitinated protein is degraded. These (and earlier) results suggest that UBP isozymes may exhibit significant substrate specificity, consistent with a role in the regulated catabolism of the polymeric ubiquitin, including the polyubiquitin protein degradation signal.

Amino Acid Sequence↗
PubMedDate not supplied

Twice-told tales of metabolic acidosis, glucocorticoids, and protein wasting: what do results from rats tell us about patients with kidney disease?

Much has been learned from animal studies in chronic renal failure that is germane to clinical studies because animal models parallel human responses. Such studies have affirmed that correction of metabolic acidosis has a favorable effect on protein metabolism, nitrogen balance and growth. In the presence of metabolic acidosis, catabolism is increased in uremia. Glucocorticoids are involved in accelerating protein degradation in muscle, which results in loss of lean body mass, while a low insulin level appears to play a permissive role in accelerating increased catabolism. Cellular mechanisms mediating these changes include upregulation of the ubiquitin-proteasome pathway and branched-chain ketoacid dehydrogenase enzyme activity in muscle. Many of these findings from rat studies have been confirmed in human studies and have important clinical implications because correction of metabolic acidosis improves nutritional status and blunts the associated increase in protein catabolism.

Acid-Base Imbalance↗