NDLI: Modulation of Lysyl Oxidase-like 2 Enzymatic Activity by an Allosteric Antibody Inhibitor

Content Provider	PubMed Central
Author	Rodriguez, Hector M. Maria, Vaysberg Mikels, Amanda Mccauley, Scott Velayo, Arleene C. Garcia, Carlos Smith, Victoria
Abstract	In this report, we assessed the steady-state enzymatic activity of lysyl oxidase-like 2 (LOXL2) against the substrates 1,5-diaminopentane (DAP), spermine, and fibrillar type I collagen. We find that both DAP and spermine are capable of activating LOXL2 to the same extent and have similar Michaelis constants (Km ∼ 1 mm) and catalytic rates (k cat ∼ 0.02 s−1). We also show that LOXL2 is capable of being inhibited by a known suicide inhibitor of lysyl oxidase (LOX), β-aminopropionitrile, which we find is a potent inhibitor of LOXL2 activity. The modality of inhibition of β-aminopropionitrile was also examined and found to be competitive with respect to the substrates DAP and spermine. In addition, we identified an antibody inhibitor (AB0023) of LOXL2 enzymatic function and have found that the inhibition occurs in a non-competitive manner with respect to both spermine and DAP. The binding epitope of AB0023 was mapped to the scavenger receptor cysteine-rich domain four of human LOXL2. AB0023 binds to a region remote from the catalytic domain making AB0023 an allosteric inhibitor of LOXL2. This affords AB0023 several advantages, because it is specific for LOXL2 and inhibits the enzymatic function of LOXL2 in a non-competitive manner thereby allowing inhibition of LOXL2 regardless of substrate concentration. These results suggest that antibody allosteric modulators of enzymatic function represent a novel drug development strategy and, in the context of LOXL2, suggest that inhibitors such as these might be useful therapeutics in oncology, fibrosis, and inflammation.
Related Links	http://dx.doi.org/10.1074/jbc.m109.094136
Ending Page	20974
Page Count	11
Starting Page	20964
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	27
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-07-02
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Modulation of Lysyl Oxidase-like 2 Enzymatic Activity by an Allosteric Antibody Inhibitor

The Enzymatic Activity of Lysyl Oxidas-like-2 (LOXL2) Is Not Required for LOXL2-induced Inhibition of Keratinocyte Differentiation

The Enzymatic Activity of Lysyl Oxidas-like-2 (LOXL2) Is Not Required for LOXL2-induced Inhibition of Keratinocyte Differentiation*

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Modulation of Lysyl Oxidase-like 2 Enzymatic Activity by an Allosteric Antibody Inhibitor

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