Peptide methionine sulfoxide reductase (Msr) is a family of
enzymes that in humans is encoded by the MSRAgene.[5][6]
Function
Msr is ubiquitous and highly conserved. Human and animal studies have shown the highest levels of expression in kidney and liver. It carries out the enzymatic reduction of
methionine sulfoxide (MetO), the oxidized form of the amino acid
methionine (Met), back to methionine, using
thioredoxin to catalyze the enzymatic reduction and repair of oxidized methionine residues.[7] Its proposed function is thus the repair of
oxidative damage to proteins to restore biological activity.[6] Oxidation of methionine residues in tissue proteins can cause them to misfold or otherwise render them dysfunctional.[7]
Clinical significance
MetO increases with age in body tissues, which is believed by some to contribute to
biological ageing.[7][8] Moreover, levels of methionine sulfoxide reductase A (MsrA) decline in aging tissues in mice and in association with age-related disease in humans.[7] There is thus a rationale for thinking that by maintaining the structureincreased levels or activity of MsrA might retard the rate of aging.
Indeed, transgenic
Drosophila (fruit flies) that overexpress methionine sulfoxide reductase show
extended lifespan.[9] However, the effects of MsrA overexpression in mice were ambiguous.[10] MsrA is found in both the cytosol and the energy-producing
mitochondria, where most of the body's endogenous
free radicals are produced. Transgenically increasing the levels of MsrA in either the cytosol or the mitochondria had no significant effect on lifespan assessed by most standard statistical tests, and may possibly have led to early deaths in the cytosol-specific mice, although the survival curves appeared to suggest a slight increase in maximum (90%) survivorship, as did analysis using
Boschloo's test, a
binomial test designed to test greater extreme variation.[10]
Deletion of this gene has been associated with
insulin resistance in mice,[11] while overexpression reduces insulin resistance in old mice.[10]
Hansel A, Heinemann SH, Hoshi T (2005). "Heterogeneity and function of mammalian MSRs: enzymes for repair, protection and regulation". Biochim. Biophys. Acta. 1703 (2): 239–47.
doi:
10.1016/j.bbapap.2004.09.010.
PMID15680232.
Picot CR, Perichon M, Cintrat JC, et al. (2004). "The peptide methionine sulfoxide reductases, MsrA and MsrB (hCBS-1), are downregulated during replicative senescence of human WI-38 fibroblasts". FEBS Lett. 558 (1–3): 74–8.
doi:
10.1016/S0014-5793(03)01530-8.
PMID14759519.
S2CID32573388.
Schallreuter KU, Rübsam K, Chavan B, et al. (2006). "Functioning methionine sulfoxide reductases A and B are present in human epidermal melanocytes in the cytosol and in the nucleus". Biochem. Biophys. Res. Commun. 342 (1): 145–52.
doi:
10.1016/j.bbrc.2006.01.124.
PMID16480945.
Peptide methionine sulfoxide reductase (Msr) is a family of
enzymes that in humans is encoded by the MSRAgene.[5][6]
Function
Msr is ubiquitous and highly conserved. Human and animal studies have shown the highest levels of expression in kidney and liver. It carries out the enzymatic reduction of
methionine sulfoxide (MetO), the oxidized form of the amino acid
methionine (Met), back to methionine, using
thioredoxin to catalyze the enzymatic reduction and repair of oxidized methionine residues.[7] Its proposed function is thus the repair of
oxidative damage to proteins to restore biological activity.[6] Oxidation of methionine residues in tissue proteins can cause them to misfold or otherwise render them dysfunctional.[7]
Clinical significance
MetO increases with age in body tissues, which is believed by some to contribute to
biological ageing.[7][8] Moreover, levels of methionine sulfoxide reductase A (MsrA) decline in aging tissues in mice and in association with age-related disease in humans.[7] There is thus a rationale for thinking that by maintaining the structureincreased levels or activity of MsrA might retard the rate of aging.
Indeed, transgenic
Drosophila (fruit flies) that overexpress methionine sulfoxide reductase show
extended lifespan.[9] However, the effects of MsrA overexpression in mice were ambiguous.[10] MsrA is found in both the cytosol and the energy-producing
mitochondria, where most of the body's endogenous
free radicals are produced. Transgenically increasing the levels of MsrA in either the cytosol or the mitochondria had no significant effect on lifespan assessed by most standard statistical tests, and may possibly have led to early deaths in the cytosol-specific mice, although the survival curves appeared to suggest a slight increase in maximum (90%) survivorship, as did analysis using
Boschloo's test, a
binomial test designed to test greater extreme variation.[10]
Deletion of this gene has been associated with
insulin resistance in mice,[11] while overexpression reduces insulin resistance in old mice.[10]
Hansel A, Heinemann SH, Hoshi T (2005). "Heterogeneity and function of mammalian MSRs: enzymes for repair, protection and regulation". Biochim. Biophys. Acta. 1703 (2): 239–47.
doi:
10.1016/j.bbapap.2004.09.010.
PMID15680232.
Picot CR, Perichon M, Cintrat JC, et al. (2004). "The peptide methionine sulfoxide reductases, MsrA and MsrB (hCBS-1), are downregulated during replicative senescence of human WI-38 fibroblasts". FEBS Lett. 558 (1–3): 74–8.
doi:
10.1016/S0014-5793(03)01530-8.
PMID14759519.
S2CID32573388.
Schallreuter KU, Rübsam K, Chavan B, et al. (2006). "Functioning methionine sulfoxide reductases A and B are present in human epidermal melanocytes in the cytosol and in the nucleus". Biochem. Biophys. Res. Commun. 342 (1): 145–52.
doi:
10.1016/j.bbrc.2006.01.124.
PMID16480945.