DSM Nutrition Cluster - Milk Genomics

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0DSM Enzyme InnovationNew tools for constructing dairy bioactivesWilliam KingOctober 20, 2010DSM Nutrition Cluster

DSM - Over a century of successful transformationsEvolutionBioterials / BiologicsLife Science ProductsPerformance 1970199020002010Technological competencesMechanical engineeringChemical engineeringPolymer technologyMaterial scienceFine chemicalsclassicalDSM Nutrition ClustermodernBiotechnology1

Who is DSM?2DSM Managing BoardCorporate StaffDSM Innovation CenterShared Competences &Business SupportNutritionPharmaPerformance MaterialsIndustrial ChemicalsDSM PharmaceuticalProductsDSM ResinsDSM AgroDSM Nutritional ProductsDSM Food SpecialtiesDSM Anti-InfectivesDSM Engineering Plastics DSM DyneemaDSM ElastomersDSM Nutrition ClusterDSM Fibre IntermediatesDSM Energy

DSM, the Life Sciences and Materials Sciences company Some 22,700 employeesNet sales 2009: 7,7 billionInnovation drivenSome 300 new patents filed in2009Strong, solid balance sheetA status for 3P reportingLeader in Dow Jones SustainabilityIndex 2009FTSE4 Good Index SeriesDSM best practice in ProductCarbon Footprint (PCF) GermanyDSM Nutrition 8%15%17%Base Chemicals& MaterialsPolymerIntermediates

The DSM Nutrition Cluster – major product areasDSM NutritionDSM Nutritional ProductsDSM Food Specialties Vitamins and carotenoids; bio-active plant extracts (eg, resveratrol) Dairy ingredients: starter cultures, coagulants, preservation ingredients Food processing enzymes (baking, fruit processing, brewing, wine making) Food safety solutions (pathogens, allergens, impurities, acrylamides) Yeast derived products (food flavors, salt replacement, fermentation) PUFA’s (ARA, DHA) for use in infant nutrition and functional food Fuctional food ingredients (functional peptides, fortification aids, etc)DSM Nutrition Cluster4

The DSM Nutrition Cluster – technology platformsDSM NutritionDSM Nutritional ProductsDSM Food Specialties Fermentation – fungal expression, bacterial expression, yeasts, dairy cultures Molecular biology – genomics, enzyme development, directed evolution Extraction and Purification – enzymes, functional ingredients, flavors, colors Chemical synthesis – organic intermediates, vitamins, supplements, colors Formulation – encapsulation, bioavailability, nano-emulsions, drying Anti-infectives – antibiotics, anti-fungals, natural antimicrobials Clinical studies – design, execution, biomarker development, publicationsDSM Nutrition Cluster5

DSM has access to a unique enzyme toolbox DSM determined the first complete DNA sequenceof the food-grade fungus Aspergillus niger Genome contains a large number of interesting genes forthe development of new enzymes, e.g.: The genome of Aspergillus niger contains 13,000 genesAbout 200 genes encode for proteasesAbout 60 of these are secreted proteases ( protein hydrolase peptidase) These are well-defined, purified, specific, single enzymes, and offerexciting possibilities for new food processes, digestive aids, food safetyapplications, and bioactive protein hydrolysates and peptides DSM holds a strong patent position on proprietary enzymes, productionprocesses, and selected applicationsDSM Nutrition Cluster6

7DSM Nutrition Cluster

Proteases in Aspergillus nigerProteolysis (total)8about 198 genes100%Cytosolic, nuclear degradation8442%Proteasome3618%Lysosomal degradation147%Vacuolar degradation2010%Other proteolytic proteins4422%Overall 198 proteases identified (intra- and extracellular)-Endo-proteases-Amino peptidases-CarboxypeptidasesDSM Nutrition Cluster

DEC consists of 2 parts 9DSM Enzyme Collection (DEC)Enzyme samplesDSM Nutrition ClusterEnzyme data

Mining the DSM Enzyme CollectionLooking for enzymes incomplex matrices?Bio-informatics SearchLooking for enzymes forsynthetic applications?Bio-diversity SearchDesign & run high throughput screensGenetic optimization, Cloning, and ExpressionDSM Nutrition Cluster

Radical Innovation in the Nutrition toProCheeseripeningPep2BalanceInfantProDSM Nutrition ClusterProtease toolboxMaxiPro, TPAP,DPAP, DiabetesInsuVitalI-OmegaTensGuard11

Enzymes offer exciting possibilities for the developmentof novel flavor & texture profiles in dairy products12 Improving taste / removing bitter off-flavoursEnzyme toolboxDi-/tripeptidasescleave after every2nd/3rd amino acid, toValrelease di- LysExoproteasescleave residues from theends of a peptide chain,to release free aminoacidsDSM Nutrition ClusterGlyLeuProteinPheLysValLysGlu AlaEndoproteasesValcleave peptide bonds in theinner regions of a peptidechain, to releaseoligopeptidesValSerAlaMetMany different functionalities Endo, Exo and tripeptidasesBroad versus narrow specificityDifferences in preference

ConfidentialNovel peptidases for cheese & dairy productsDSM Nutrition Cluster

Accelerzyme CPG is a ptidase (Accelerzyme CPG)DEndo-protease (Accelerzyme NP)GDSM Nutrition ClusterCOOH

Accelerzyme assisted ripeningAccelerzyme CPGRipening accelerator Reduction cheesematuration time therebyreducing storage time andcosts Eliminates bitter peptidesin cheese, proteinhydrolysatesprocessed cheese, EMC50%Storage Time Reduction Softening soft cheeses(Brie, Camembert) Speed-up blue fungusgrowth in Blue Cheese 15/ month/ tonne of cheese Increased flavordevelopment fermentedmeatDSM Nutrition Cluster15

Enzymes offer exciting possibilities for the developmentof novel flavor & texture profiles in dairy products16 Improving taste / removing bitter off-flavours Improving yields, color, and gelation propertiesβ-caroteneDSM Nutrition ClusterEnzyme toolbox

ConfidentialEnzymatic bleaching of dairy productsDSM Nutrition Cluster

Application: Control of products colorMozzarella, Feta and Ricotta cheeses made from cow milkWheyDSM Nutrition ClusterWhipped creamConfidential18

Carotenoid degrading fungal enzymesConfidential19 Cyathus palidus X Ischnoderma benzoinum XScreening on β-carotene agar plates Marasmius scordonius (MsP) ! Trametes versicolor X Lepista irina XDSM Nutrition ClusterLight halo around Marasmiusscrodonius growing colony

Novel texturizing tools for dairy protein applicationsEnzymatic cross linking of dairy proteinsDSM Nutrition Cluster

Use of Lysyl oxidase21- Reduction of milkprotein (whey) up to 50% giving same (or higher)viscosity in final yoghurt- Treatment of milk protein prior to adding in yoghurt process- Adding milk protein to milk, LOX treatment, pasteurization, cultures Î yoghurt7 /ton profitLOX costs 10%0.25 centValue-basedPricing will beapplied0.8% milkpowderc.i.u. 2.5 cent / liter 0.5% milkpowderc.i.u. 1.5 cent / liter- Reduction of caloric value of yoghurt-Other applications (IceCream, Soy-based applications)DSM Nutrition Cluster

Enzymes offer exciting possibilities for the developmentof novel flavor & texture profiles in dairy products Improving taste / removing bitter off-flavours Improving yields, color, and gelation properties Improving food digestibility and DiseaseDSM Nutrition Cluster22

AN-PEP : an enzyme to degrade gluten epitopes- cleaves peptides after a proline residueAspergillus niger- active at low (gastric) pHprolyl endoproteaseToxic gluten proteinImmune response inceliac patientsDSM Nutrition ClusterNon-Toxic gluten peptidesImmune response inceliac patients23

Enzymatic activity [%]Enzymatic activity [%]An-PEP optimized for stability to stomach NT0'15' 30' 60'AN-PEPAN-PEP / pH 2 / pepsinFM-POPFM-POP / pH 2FM-POP / pH 2 / pepsinStepniak D et al. Am J Physiol Gastrointest Liver Physiol, 2006; 291: G621-9DSM Nutrition Cluster24

Enzymes offer exciting possibilities for the developmentof novel flavor & texture profiles in dairy products 25Improving taste / removing bitter off-flavoursImproving yields, color, and gelation propertiesImproving digestibility and food safetyDevelopment of new bioactive peptidesEnzyme toolboxDi-/tripeptidasescleave after every2nd/3rd amino acid, toValrelease di- LysExoproteasescleave residues from theends of a peptide chain,to release free aminoacidsDSM Nutrition ClusterGlyLeuProteinPheLysValLysGlu AlaEndoproteasesValcleave peptide bonds in theinner regions of a peptidechain, to releaseoligopeptidesValSerAlaMetMany different functionalities Endo, Exo and tripeptidasesBroad versus narrow specificityDifferences in preference

Release of bioactive peptides using novel DSM enzymes Milk proteins are known to contain manybiologically active peptides & glycopeptidesReleasing the bioactive peptidesin proteinsProtein Bioactive peptides are inactive in theirnative protein carrier – they are releasedthrough bacterial or enzymatic action26LeuProGlnGluProProProProMetValGlyValLys Both human and bacterial proteases maybe active in releasing bio-actives from milkand colostrum Bioactive peptides are being discovered bygenomic characterization, supported by theInternational Milk Genomics ConsortiumDSM Nutrition eAlaMetProProSerLeuGluArg

Example of functional peptides in β-casein27Antihypertensive yGluIleValGluSerPLeuSerP SerP nValValProThrIleSerLeuValTyrProPheProβ casomorphine 11AntihypertensiveValArgβ casomorphine HisSerβ -casokinin M Nutrition ClusterGlyArgValProGlyLeuValProGluGlnTyrLeuLeu

PeptoPro beverages for sports recovery28 Muscle glycogen resynthesis is one of the most important factorswhich determine the time needed to recover from exercise, andeventually energy and performance levels. With regular sport drinks, it takes about 20hours to restore energy levels Athletes need to recover within 12 hours inorder to be able to perform the next day PeptoPro sports accelerates uptake of theglucose in the muscle cells and improvesmuscle glycogen resynthesisDSM Nutrition Cluster

Selected peptides behave as ACE inhibitorsAngiotensin I converting enzymeXZn C2H5OCHCH3CH C NOCHCH C NOO-CNC OIPPIC50 2 μMO-OCNC OVPPIC50 9 μMLPPIC50 10 μMNH2CH3OCH CH2 CH C NCH3 These dairy peptides are:1) resistant to digestion2) small enough to pass theintestinal barrier, and3) with strong ACE inhibitoryproperties.NH2CH3CH3H29NH2DSM Nutrition ClusterO-OCNC O

TensGuard – a source of Lactotripeptides Casein contains high levels of ACEinhibitor peptides. These peptides are largely degradedby stomach enzymes before reachingthe intestinal tract Controlled digestion of casein withDSM endo-proteases releases the tripeptides without loss of BioactivepeptidesProLeuEnzymeLactotripeptides (mg/g 1,81,11,44.33,2 M developed clean flavor formulations with high levels of LactotripeptidesDSM Nutrition ClusterMetLysArgPheValProGluProProGluArg

Tensguard bioavailability and absorptionIle-Pro-Pro (pmol/L) Human volunteers ingested a yogurt drink enriched with IPP and VPP. Bloodplasma samples were collected and analyzed for IPP and VPP The presence of IPP, but not VPP, was demonstrated in measurable amountsin the circulation Tensguard contains high levels of IPP, the most effective of the ACE peptides1000Lactotripeptideenriched drinkPlacebo drink8006004002000DSM Nutrition Cluster306090120Time (min)Foltz et al (2007), Journal of Nutrition 137, 953-931

Balancing of blood sugar peaks32 InsuVital restores the impaired insulin function in type 2 diabetes It works by helping your body release insulin right at the start of a meal, when you need itthe most. Better meal time glucose control lowers your overall level of blood sugarBlood suger levels InsuVital works on complementary to medication. It is not intended to replacemedication, but is a nutritional intervention to lower glucose peaks.DSM BreakfastNutrition Cluster ingInsuVitalHealthypeopleLunchDinner

33 InsuVital is a casein hydrolysate that lowers postprandial glucose peaks byimproving the impaired insulin secretion in type 2 diabetes An art-13 dossier to substantiate health claims has been submittedpromotes healthy blood sugar levelslowers postprandial blood sugar to healthy levelshelps to regulate blood sugar peaks after a meal Safe; extensive history of safe use DSM has own IP to claim blood glucose regulation by protein hydrolysates InsuVital can be applied in a wide variety of products within the functional food ormedical nutrition range Current observed/expected customer and consumer interest is highDSM Nutrition Cluster

Where we are today . . .34 DSM’s large gene bank and high throughput screening are potent capabilitiesfor the creation of new food grade enzymes. New enzymes lead to innovation in food processing, functionality, and safety New enzymes can lead to new bio-active ingredients for nutrition, metabolichealth, and for treatment of specific chronic conditions. It has been shown that bioactive peptides can survive digestion and beabsorbed into the blood stream – dosages can be measured and controlled. Taste, purification, and bioavailability issues can be overcome with novelenzymes, refining, chromatography and formulation. Bioactive peptides from milk demonstrate clinically significant effects – astarting point that may lead to targeted nutrition and medical foods.DSM Nutrition Cluster

Peering into the future . . .35 Conserved sequences in mammalian milk suggest a range of new functionalpossibilities for nutrition & health – satiety, immune function, etc. Genomic characterization of mammalian and human milk is starting toidentify new bio-actives embedded in casein and whey protein fractions. New analytical tools are discovering bio-active components in other milkfractions, eg, phospholipids, oligosaccharides, lipoproteins, sugars, etc. Enzymes will be essential tools to releasing this potential for commercialapplications. DSM supports Open Innovation by partnering with dairy processors, DMI,Dairy Centers, and universities.DSM Nutrition Cluster

What we need from the research world . . .36 Ongoing genomic characterization and annotation of key mammalian and human milkgenes, especially those coding for novel enzymes and proteins. Better phylogenetic understanding of high value enzymes and proteins – how and whyhave key components changed during mammalian evolution. Genomic and functional characterization of conserved milk components, eg,conserved peptides embedded in milk protein. Isolation and characterization of potential bioactive components Effects of potential bioactives on gene expression (in vitro) Linkage of bioactives to specific nutrition, development, or health effects. Effect of potential bioactives on the microbiome. Bio-availability and gastro-intestinal uptake of potential bioactives. Clinical evalution and validation of selected bio-actives. DSM supports the development and commercialization of new functional ingredientsfor food processing, nutrition, and health. The best place to find these ingredients is in nature’s most evolved food.DSM Nutrition Cluster

Ingredients for food, nutrition, and healthThe EndThe StartDSM Nutrition Cluster37

DSM Managing Board. DSM Innovation Center. Corporate Staff. Shared Competences & Business Support. DSM Nutritional Products. DSM Food Specialties. DSM Resins. DSM Engineering Plastics-DSM Dyneema. DSM Elastomers. DSM Agro. DSM Fibre Intermediates. DSM Pharmaceutical Products.

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