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Genetic Diversity in Proteolytic Enzymes and Amino Acid Metabolism Among Lactobacillus Helveticus Strains1

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Genetic Diversity in Proteolytic Enzymes and Amino Acid Metabolism Among Lactobacillus Helveticus Strains1 J. Dairy Sci. 94 :4313–4328 doi: 10.3168/jds.2010-4068 © American Dairy Science Association®, 2011 . Genetic diversity in proteolytic enzymes and amino acid metabolism among Lactobacillus helveticus strains1 J. R. Broadbent ,*2 H. Cai ,† R. L. Larsen ,* J. E. Hughes ,‡ D. L. Welker ,‡ V. G. De Carvalho ,§ T. A. Tompkins ,§ DQG-/6WHHOHۅ1HYLDQL)ۅDWWL*0ۅUG|)9RJHQVHQ$'H/RUHQWLLV$> * Department of Nutrition, Dietetics, and Food Sciences and Western Dairy Center, Utah State University, Logan 84322-8700 † Department of Food Science, University of Wisconsin–Madison 53706 ‡ Department of Biology, Utah State University, Logan 84322-5305 § Institut Rosell, Montreal, QC, Canada H4P 2R2 # University of Copenhagen, Rolighedsvej 30, DK-1958 Frederiksberg C, Denmark \HSDUWPHQWRI*HQHWLFV%LRORJ\RI0LFURRUJDQLVPV$QWKURSRORJ\(YROXWLRQ8QLYHUVLW\RI3DUPD9LDOH8VEHUWL$3DUPD,WDO'ۅ ABSTRACT and Sjöström, 1975; Bartels et al., 1987a,b; Ardö and Pettersson, 1988; Drake et al., 1996). Moreover, milk Lactobacillus helveticus CNRZ 32 is recognized for fermented with certain Lb. helveticus strains has been its ability to decrease bitterness and accelerate flavor shown to become enriched with antihypertensive and development in cheese, and has also been shown to immunomodulatory bioactive peptides (Laffineur et al., release bioactive peptides in milk. Similar capabilities 1996; LeBlanc et al., 2002; Hayes et al., 2007b; Gob- have been documented in other strains of Lb. helveticus, betti et al., 2010). Although Lb. helveticus is commonly but the ability of different strains to affect these char- associated with milk environments, this species has also acteristics can vary widely. Because these attributes been recovered from whisky fermentations (Cachat and are associated with enzymes involved in proteolysis Priest 2005; Naser et al. 2006) and, more sporadically, or AA catabolism, we performed comparative genome from the human reproductive or gastrointestinal tracts hybridizations to a CNRZ 32 microarray to explore the (Anukam et al. 2006; Stoyancheva et al. 2006; Vitali et distribution of genes encoding such enzymes across a al. 2010). bank of 38 Lb. helveticus strains, including 2 archival Lactobacillus helveticus is auxotrophic for several AA samples of CNRZ 32. Genes for peptidases and AA (Kandler and Weiss, 1986; Christensen and Steele, 2003; metabolism were highly conserved across the species, Christiansen et al., 2008), so rapid growth in milk or whereas those for cell envelope-associated proteinases other environments that contain low levels of free AA varied widely. Some of the genetic differences that were relies on a complex proteolytic enzyme system whose detected may help explain the variability that has been collective function involves the procurement of essen- noted among Lb. helveticus strains in regard to their tial AA needed for growth (Christensen et al., 1999). functionality in cheese and fermented milk. Detailed analysis of the proteolytic enzyme system in Key words: Lactobacillus , proteolysis , cheese flavor , dairy LAB, most notably Lactococcus lactis and Lb. hel- bioactive peptide veticus, has shown that enzymes involved in the release of essential AA from large proteins such as CN can be INTRODUCTION loosely divided into 3 major categories: (1) an extracel- lular, cell envelope-associated proteinase (CEP) that Lactobacillus helveticus is an obligately homofer- hydrolyzes CN into oligopeptides; (2) specialized trans- mentative lactic acid bacterium (LAB) that is widely port systems to take up those oligopeptides, as well as used as a starter culture to manufacture yogurt and di- and tripeptides, and free AA that may be present certain Swiss and Italian cheeses (Hassan and Frank, in the medium; and (3) intracellular endopeptidases 2001; Gatti et al., 2004), and also as a flavor-enhancing and exopeptidases, including many that are specific for adjunct culture for other cheese types (Pettersson proline-containing peptides, which degrade internalized peptides into di- and oligopeptides and free AA (Chris- Received December 6, 2010. tensen et al., 1999; Savijoki et al., 2006). Accepted April 23, 2011. Although the biological role of the proteolytic en- 1 This communication is approved as UAES Journal Paper Number zyme system is directed toward cellular growth needs, 8273. Peggy Steele, a member of J. L. Steele’s family, is employed by Danisco Inc. (Copenhagen, Denmark), a supplier of bacterial cultures the actions of these enzymes in cheese and fermented to the food industry. foods has important practical consequences on the sen- 2 Corresponding author: [email protected] sory, functional (stretch, melt), and bioactive attributes 4313 4314 BROADBENT ET AL. of these products (Oommen et al., 2002; Broadbent and genes involved in proteolysis and AA catabolism among Steele, 2007; Hayes et al., 2007a). Moreover, subsequent a bank of Lb. helveticus strains isolated from different conversion of some free AA into volatile and nonvolatile sources. compounds by LAB in cheese is believed to represent the rate-limiting step in the development of mature MATERIALS AND METHODS flavor and aroma (Yvon and Rijnen, 2001; Ardö, 2006). Comparative Genome Hybridizations For these reasons, the relationship between proteolytic enzyme activity and dairy foods quality has been a fo- Lactobacillus helveticus strains used in this study for cal point of dairy research for decades. CGH were selected to provide broad representation Studies in the field have shown a variety of LAB may of the ecological and industrial diversity in this spe- contribute to these reactions and properties (Fox, 1989; cies (Table 1). Industrial strains and whiskey isolates Gobbetti et al., 2002; Azarnia et al., 2006; Cogan et were obtained from culture collections at Utah State al., 2007; Hayes et al., 2007b) and that the proteolytic University, the University of Wisconsin-Madison, the enzymes found in these cells are, for the most part, University of Copenhagen, the Centre National de distributed across all dairy LAB (Christensen et al., Recherche Zootechnique, and the Institut Rosell. The 1999; Savijoki et al., 2006; Liu et al., 2010). However, UPR natural starter strains were isolated at the Uni- broad differences in specificity and relative activity of versity of Parma from Grana Padano, Provolone, or individual enzymes exist, with lactobacilli generally Parmigiano Reggiano cheese whey, or fresh Parmigiano showing higher proteolytic activity than other types of Reggiano curd (Table 1), essentially as described by LAB (Sasaki et al., 1995; Gilbert et al., 1997; Weimer Gatti et al. (2003). et al., 1997; Laan et al., 1998). Lactobacilli also possess Stock cultures were maintained at −80°C in de Man, a greater number and diversity of genes for proteinases Rogosa, Sharpe (MRS) broth (Difco Laboratories, and peptidases. Only lactobacilli, for example, have Detroit, MI) with 20% (vol/vol) glycerol. Working cul- been found to possess more than one gene for CEP, tures were prepared from stock cultures by 2 successive and these bacteria also show greater redundancy in the transfers (1% inocula) in MRS broth at 37°C for 16 to number of genes for di- and tripeptidases and for endo- 18 h. Comparative genome hybridization experiments peptidase PepO (Pederson et al., 1999; Sridhar et al., were performed using an Affymetrix (Affymetrix Inc., 2005; Liu et al., 2010). Lactobacilli also have genes for Santa Clara, CA) custom microarray designed to in- several endo- and aminopeptidases, including oligoen- clude eleven 24-mer probes for each of 2,387 predicted dopeptidases PepE and PepG, proline iminopeptidase coding sequences (CDS, including pseudogenes) in the PepI, prolyl aminopeptidase PepL, and prolinase PepR, Lb. helveticus CNRZ 32 genome, as well as all non- which have not been found in Lc. lactis or Streptococcus redundant CDS in the Lactobacillus casei ATCC 334 thermophilus (Christensen et al., 1999; Savijoki et al., genome (Cai et al., 2009). The only CDS not included 2006; Liu et al., 2010). in the microarray design were duplicate copies of rRNA Among lactobacilli, Lb. helveticus is especially rec- and transposase-encoding genes found in each species. ognized for its active protease and peptidase activities Genomic DNA for CGH was extracted from each toward milk proteins (Gilbert et al., 1997; Christensen strain using a MasterPure Gram-Positive DNA Puri- et al., 1999; Matar et al., 2001; Savijoki et al., 2006), fication Kit (Epicentre Biotechnologies, Madison, WI). and the most thoroughly characterized proteolytic en- Five micrograms of genomic DNA was fragmented and zyme system in Lb. helveticus belongs to strain CNRZ labeled according to instructions for labeling mRNA 32 (reviewed by Christensen et al., 1999; plus Pederson for antisense prokaryotic arrays (Affymetrix Inc.). et al., 1999; Chen et al., 2003; Christensen and Steele Reactions for hybridization contained 1 μg of labeled 2003; Sridhar et al., 2005; Smeianov et al., 2007). Lacto- DNA and were performed using the fully automated bacillus helveticus CNRZ 32 is an industrial bacterium components (Fluidics Station 450 and GeneChip Scan- that decreases bitterness and accelerates cheese flavor ner 3000) of an Affymetrix GeneChip System operated development, and has also been shown to be capable of by staff in the Utah State University Center for Inte- producing anti-hypertensive peptides in milk (Bartels grated Biosystems (Logan, UT). Statistical analysis of et al., 1987a,b; Christensen et al., 1999; Savijoki et al., microarray data
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