Journal
BIOCHEMISTRY
Volume 45, Issue 12, Pages 3961-3971Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi052339+
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Funding
- NHLBI NIH HHS [R01 HL086798-01, P01 HL030086, P01 HL030086-21A19008, P50 HL073996, HL078527, R01 HL086798, HL075381, R01 HL075381, R01 HL078527] Funding Source: Medline
- NIDDK NIH HHS [P01 DK002456-380020, P30 DK056341-019003, P30 DK056341-05S2, P30 DK056341-06, P01 DK002456-389003, P30 DK035816, P30 DK056341, P01 DK002456-439003, P01 DK002456, P01 DK002456-430020] Funding Source: Medline
- NIEHS NIH HHS [P30 ES073996] Funding Source: Medline
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Most studies of protein oxidation have typically focused on the reactivity of single amino acid side chains while ignoring the potential importance of adjacent sequences in directing the reaction pathway. We previously showed that hypochlorous acid (HOCl), a specific product of myeloperoxidase, inactivates matrilysin by modifying adjacent tryptophan and glycine (WG) residues in the catalytic domain. Here, we use model peptides that mimic the region of matrilysin involved in this reaction, VV (WG) under bar TA, VV (WA) under bar TA, and the library VV (WX) under bar TA, to determine whether specific sequence motifs are targeted for chlorination or oxygenation by myeloperoxidase. Our results demonstrate that HOCl generated by myeloperoxidase or activated neutrophils converts the peptide VV (WG) under bar TA to a chlorinated product, WG+32-(Cl). Tandem mass spectrometry in concert with high resolution H-1 and two-dimensional NMR analysis revealed that the modification required cross-linking of the tryptophan to the amide of glycine followed by chlorination of the indole ring of tryptophan. In contrast, when glycine in the peptide was replaced with alanine, the major products were mono- and dioxygenated tryptophan residues. When the peptide library VV (WX) under bar TA (where X represents all 20 common amino acids) was exposed to HOCl, only WG produced a high yield of the chloroindolenine derivative. However, when glycine was replaced by other amino acids, oxygenated tryptophan derivatives were the major products. Our observations indicate that WG may represent a specific sequence motif in proteins that is targeted for chlorination by myeloperoxidase.
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