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WO 2009/126841 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 15 October 2009 (15.10.2009) WO 2009/126841 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12Q 1/68 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, PCT/US2009/040121 EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (22) International Filing Date: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, 9 April 2009 (09.04.2009) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, (25) Filing Language: English NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, (26) Publication Language: English SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 12/100,308 9 April 2008 (09.04 .2008) US (84) Designated States (unless otherwise indicated, for every 12/358,140 22 January 2009 (22.01 .2009) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): COL¬ ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, ORADO STATE UNIVERSITY RESEARCH FOUN¬ TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, DATION [US/US]; PO Box 483, Fort Collins, CO 80522 ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (US). MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, (72) Inventor; and MR, NE, SN, TD, TG). (75) Inventor/Applicant (for US only): REARDON, Ken¬ neth, F. [US/US]; 4901 Deertrail Court, Fort Collins, CO Published: 80526 (US). — with international search report (Art. 21(3)) (74) Agent: MARSHALL, Shireen; Lathrop & Gage LLP, 4845 Pearl East Circle, Suite 201, Boulder, CO 80301 (US). (54) Title: ENZYMATIC BIOSENSORS WITH ENHANCED ACTIVITY RETENTION FOR DETECTION OF ORGANIC COMPOUNDS Enzyme Membrane pH-FET FIG. 10 (57) Abstract: Enzymatic biosensors and methods of producing distal tips for biosensor transducers for use in detecting one or more analytes selected from organic compounds susceptible to dehalogenation, organic compounds susceptible to oxygenation, organic compounds susceptible to deamination, organosulfate compounds susceptible to hydrolysis, and organophosphate com pounds susceptible to hydrolysis are disclosed herein, as well as biosensor arrays, methods of detecting and quantifying analytes within a mixture, and devices and methods for delivering reagents to enzymes disposed within the distal tip of a biosensor. ENZYMATIC BIOSENSORS WITH ENHANCED ACTIVITY RETENTION FOR DETECTION OF ORGANIC COMPOUNDS RELATED APPLICATIONS [0001] This application claims the benefit of priority of U.S. Patent Application Serial No. 12/100,308, filed April 9, 2008, and U.S. Patent Application Serial No. 12/358,140, filed January 22, 2009. Each of these applications is incorporated by reference herein. GOVERNMENT RIGHTS [0002] This invention was made with Government support under contract number BES-0529048 awarded by the National Science Foundation and contract number DACA71- Ol-C-0009 awarded by the U.S. Army Research Office. The U.S. Government has certain rights in this invention. BACKGROUND [0003] A biosensor contains a biological component (e.g., enzyme, antibody, DNA/RNA, aptamer) coupled to a transducer, which is typically a physical sensor, such as a microcantilever, or a chemical sensor, such as a pH electrode, that produces a signal proportional to analyte concentration. The analyte is normally detected by the biocomponent through a chemical reaction or physical binding. For example, in the case of an enzyme biosensor, a product of the enzyme-catalyzed reaction, such as oxygen, ammonia, hydrochloric acid or carbon dioxide, may be detected by an optical or electrochemical transducer. [0004] Enzymes are preferred biocomponents because they are catalytic, specific to a particular substrate (analyte) and fast acting. Generally, enzymes for use in a biosensor may be disposed within whole cells or extracted from cells and purified. Whole cells are less expensive than purified enzymes and may provide an environment for longer enzyme stability, but cell-based biosensors typically have longer response times and less specificity to a single analyte than purified enzymes due to the presence of multiple enzymes within the cells. Whole-cell biosensors may utilize dead cells or living cells; the later may require proper control of environment and maintenance to retain their efficacy. [0005] The use of purified enzymes in biosensors has also been explored. In D.W. Campbell, "The Development of Biosensors for the Detection of Halogenated Groundwater Contaminants." Spring 1998, Colorado State University, Fort Collins, Colorado, reference is made to a pH optode featuring the reaction illustrated schematically in FIG. 2.4 of Campbell: the cleavage of halide ion X and proton H+ from a halogenated hydrocarbon by the appropriate hydrolytic dehalogenase. An earlier reference, C. Mϋller, F. Schubert and T. Scheper, Multicomponent fiberoptical biosensor for use in hemodialysis monitoring, SPIE Proc, Vol. 2131, Biomedical Fiber Optic Instrumentation, Los Angeles, CA, USA (1994) ISBN 0-8194-1424-7, pp. 555-562, employed a pH optode-type biosensor limited to the use of urease as a catalyst (urea is split into ammonia & CO2) : the bifunctional reagent glutaraldehyde was used to bind urease directly to the head of a pH optode. These examples demonstrate the feasibility of utilizing purified enzymes in biosensors with the advantage that the enzymes are not exposed to proteases, found in whole cells, that degrade intracellular proteins. However, extraction, isolation and purification of a particular enzyme can be expensive, tedious and complicated, as well as cause the enzyme to lose a high percentage of its activity. [0006] In addition to the particular circumstances affecting whole cells and purified enzymes discussed above, there are two important challenges to the overall development of enzyme-based biosensors. First, the resolution of similar analytes within a mixture has proven difficult. Although enzymes are generally considered specific, most have activity toward similar molecules within the same chemical family. Second, biosensors containing enzymes that require a cofactor, such as nicotinamide adenine dinucleotide (NADH), have limited lifetimes because cofactors, which are consumed during enzyme- catalyzed detection of an analyte, must be regenerated. The supply of cofactors, either through an ancillary reaction that occurs outside the cell or a metabolic process within a living cell, is non-trivial and has hindered the development of biosensors that require cofactors. SUMMARY [0007] The present instrumentalities advance the art and overcome the problems discussed above by providing biosensors and methods of producing distal tips for biosensor transducers for use in detecting one or more analytes selected from organic compounds susceptible to dehalogenation, organic compounds susceptible to oxygenation, organic compounds susceptible to deamination, organosulfate compounds susceptible to hydrolysis, and organophosphate compounds susceptible to hydrolysis. [0008] In an embodiment, a distal tip of a biosensor transducer for use in detecting an organic compound susceptible to deamination includes a biocomponent comprising one or more enzymes for carrying out deamination of the organic compound. [0009] In an embodiment, a distal tip of a biosensor transducer for use in detecting an organic compound susceptible to deamination includes a biocomponent comprising at least one enzyme selected from the group consisting of hydrolases from EC family 3.5 and lyases from EC family 4.3 for carrying out deamination of the organic compound. [0010] In an embodiment, a distal tip of a biosensor transducer for use in detecting organic compounds includes a biocomponent comprising at least one enzyme selected from the group consisting of hydrolases from EC family 3.5 and lyases from EC family 4.3 for carrying out deamination of one organic compound; and one or more of (i) an oxygenase from EC family 1.13 for carrying out an oxidation of one organic compound, (ii) an oxygenase from EC family 1.14 for carrying out an oxidation of one organic compound, (iii) a dehalogenase for carrying out dehalogenation of one organic compound, and (iv) a hydrolase from subclass EC 3.1 for carrying out a hydrolysis of one organic compound. [0011] In an embodiment, a distal tip of a biosensor ion-sensing transducer for use in detecting an analyte comprising an organophosphate compound includes a biocomponent comprising a hydrolase selected from subclass EC 3.1, which has been treated to maintain a period of enzymatic efficacy, for carrying out hydrolysis of the compound. [0012] In each of the embodiments above, the biocomponent is immobilized to a surface of the tip by one or more of (a) entrapment within a hydro gel; (b) entrapment within a polymeric network; (c) encapsulation; (d) covalent bonding; and (e) adsorption. The biocomponent is further stabilized to the tip by one or more of crosslinking a surface of the immobilized biocomponent, crosslinking a polymer layer to the biocomponent, adding a gel- hardening agent to the biocomponent, adding a stabilizing agent to the biocomponent, and modifying a component used to immobilize the biocomponent to the surface of the tip. BRIEF DESCRIPTION OF THE DRAWINGS [0013] FIG. 1 is a depiction of several pathways derived from general knowledge of the degradation of atrazine. [0014] FIG. 2 depicts a hydrolytic dehalogenation of atrazine using atrazine chlorohydrolase. [0015] FIG. 3 schematically depicts features of a known system suitable for use in connection with a pH optode as the transducer (Campbell, 1998).
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