diff --git a/content/attachments/Pasted image 20251209111439.png b/content/attachments/Pasted image 20251209111439.png new file mode 100644 index 0000000..464ff9e Binary files /dev/null and b/content/attachments/Pasted image 20251209111439.png differ diff --git a/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/Slides.pdf.pdf b/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/Slides.pdf.pdf new file mode 100644 index 0000000..c6cad1e --- /dev/null +++ b/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/Slides.pdf.pdf @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:3acb4af4f5b1f2f38a75535f17356f8efceaf45400e6136580950d1b2ad5b9ea +size 2445104 diff --git a/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/đŸ‘šđŸ»â€đŸ« Slides.md b/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/đŸ‘šđŸ»â€đŸ« Slides.md index e35c770..a4051cc 100644 --- a/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/đŸ‘šđŸ»â€đŸ« Slides.md +++ b/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/đŸ‘šđŸ»â€đŸ« Slides.md @@ -6,3 +6,315 @@ tags: förelĂ€sare: Martin Lidell date: 2025-12-09 --- +Nukleotidnedbrytning +LPG001 +Martin Lidell + +--- + +## Lecture outline + +- Nucleotides – short repetition of structural parts +- Functions of nucleotides +- Degradation of nucleic acids from food sources +- Degradation of purine nucleotides +- Degradation of pyrimidine nucleotides +- Two diseases related to purine nucleotides + - Gout – a very common disease + - Adenosine deaminase deficiency – a very rare disease + +--- + +## What is a nucleotide? + +- Nucleotide = Phosphate(s) + Pentose + Nitrogenous base +- Nucleoside = Pentose + Nitrogenous base +- Adenosine monophosphate +- OH (in ribose) or H (in deoxyribose) + +--- + +## The nitrogenous bases – purines and pyrimidines + +- Five bases +- PURINES: Purine, Adenine, Guanine +- PYRIMIDINES: Pyrimidine, Cytosine, Uracil (in RNA), Thymine (in DNA) +- Two rings; two purines +- Three pyrimidines; pyramide from above; CUT + +--- + +## Functions of nucleotides – some examples + +- Building blocks for DNA and RNA (store and translate genetic information) +- Building blocks for important biomolecules (e.g. Coenzyme A) +- Signaling molecules (both extra- and intracellular) (e.g. cAMP, adenosine signaling – a nucleoside) +- “Activators” of biomolecules used for biosynthesis + - UDP-Glucose (activated form of glucose; glucose donor in glycogen synthesis) + +--- + +## Overview of nucleotide metabolism + +- Nucleotides + - De novo synthesis + - Salvage synthesis (synthesis from reused nitrogenous bases and sugars) + - DNA and RNA synthesis + - Conversion to other important biomolecules + - Degradation + +- From degradation: + - Nitrogenous bases → + - Reuse for nucleotide synthesis (salvage) + - Further degradation → + - Purines → Urate + Urea + - Pyrimidines → Urea + Energy or energy-rich molecules + - Sugar moiety → + - Reuse for nucleotide synthesis (salvage) + - Energy source (ATP or energy-rich molecules) + +--- + +## Expensive with de novo synthesis of nucleotides – the salvage pathway is cheaper + +- De novo pathway vs salvage pathway +- PRPP; 5-Phosphoribosyl 1-pyrophosphate + +--- + +## Degradation of nucleic acids from food sources + +- Degradation of dietary nucleic acids occur in the small intestine +- Nucleases, secreted by the pancreas, hydrolyze RNA and DNA to oligonucleotides +- Oligonucleotides are further hydrolyzed by pancreatic phosphodiesterases, producing mononucleotides +- In the intestinal mucosal cells (intestinal epithelial cells), nucleotidases remove the phosphate groups, releasing nucleosides that are further degraded to free bases and sugars by nucleosidases +- The liberated bases can potentially be used in salvage pathways for nucleotide synthesis (however, at least the purines appear to be degraded to a large extent already in the intestinal cells) + +--- + +## Nucleotide degradation pathways + +- Nucleotides → Degradation → + - Nitrogenous bases → + - Reuse for nucleotide synthesis (salvage) + - Further degradation → + - Purines → Urate + Urea + - Pyrimidines → Urea + Energy or energy-rich molecules + - Sugar moiety → + - Reuse for nucleotide synthesis (salvage) + - Energy source (ATP or energy-rich molecules) + +--- + +## Degradation of purine nucleotides – formation of uric acid + +- GMP → (via nucleotidases) → Guanosine +- Nucleotidases convert the nucleotides into nucleosides +- Guanosine → Guanine (and further degradation) +- Pathway towards hypoxanthine, xanthine and uric acid + +--- + +## Adenosine deaminase – an important enzyme in the degradation of adenosine + +- Adenosine is deaminated to inosine by adenosine deaminase +- Toxic ammonia converted into urea in the liver +- Parallel pathway: GMP → Guanosine → Guanine, etc. + +--- + +## The sugar parts are removed by nucleoside phosphorylase + +- GMP → Guanosine +- Sugar phosphates options: + 1. Reuse for nucleotide synthesis (convert to PRPP) + 2. Use for energy production or generation of energy-containing molecules +- The sugar parts are removed by nucleoside phosphorylase + +--- + +## GMP and AMP degradation converge at the level of xanthine that is further metabolized to uric acid + +- Toxic ammonia converted into urea in the liver +- Uric acid (urate) excreted in the urine + +--- + +## Degradation of pyrimidine nucleotides + +- Pathways for CMP, UMP and dTMP +- Intermediates within brackets refer to metabolites from dTMP degradation + +--- + +## CMP and UMP degradation converge at the level of uridine + +- Nucleotidases convert the nucleotides into nucleosides +- CMP, UMP → Uridine +- Toxic ammonia converted into urea in the liver + +--- + +## The sugar part is removed by a phosphorylase to generate the free pyrimidine bases + +- Options for sugar phosphates: + 1. Reuse for nucleotide synthesis (convert to PRPP) + 2. Use for energy production or generation of energy-containing molecules + +- Options for free bases: + 1. Reuse for nucleotide synthesis + 2. Use for energy production (ATP) or generation of energy-containing molecules + +--- + +## Complete degradation of nitrogenous bases for ATP production or generation of energy-containing molecules + +- From CMP and UMP: + - Acetyl CoA (Propionyl CoA) → ATP, fatty acids or ketone bodies +- From dTMP: + - Succinyl CoA (CAC intermediate) → ATP or glucose production +- Enzymes/intermediates: + - Methylmalonate semialdehyde dehydrogenase + - Propionyl CoA carboxylase + - Methylmalonyl CoA + - Methylmalonyl CoA mutase +- Toxic ammonia converted into urea in the liver + +--- + +## What happens with the sugar moiety produced during nucleotide degradation? + +- Ribose-1-phosphate ↔ (Phosphopentomutase) ↔ Ribose-5-phosphate +- Deoxyribose-1-phosphate ↔ Deoxyribose-5-phosphate +- Ribose-5-phosphate can enter the pentose phosphate pathway (transketolase and transaldolase) +- Deoxyribose-5-phosphate → (Deoxyribose phosphate aldolase) → Glyceraldehyde-3-phosphate + Acetaldehyde +- Fructose-6-phosphate + Glyceraldehyde-3-phosphate → glycolysis/gluconeogenesis connection +- Acetyl CoA from acetaldehyde → ATP, fatty acids or ketone bodies +- Can be reused for nucleotide synthesis (converted to PRPP) + +Endproducts used for energy production or generation of energy-containing molecules: + +- Fructose-6-phosphate and glyceraldehyde-3-phosphate: ATP or glucose production +- Acetyl CoA: ATP, fatty acids or ketone bodies + +--- + +## Full degradation of pyrimidines and purines + +**Pyrimidines** + +- Generate ammonia (NH₃) that is converted into UREA by the liver and excreted in the urine +- Metabolites that can be used for energy production (ATP) or converted into energy-containing molecules such as glucose (liver), fatty acids and ketone bodies + +**Purines** + +- Primarily generate URIC ACID (urate) that is excreted in the urine +- Some ammonia is also produced; converted into urea by the liver + +--- + +## Gikt – frĂ„n ”the disease of kings” till folksjukdom + +- Vid för höga uratnivĂ„er i blodet (>6–7 mg/dl) fĂ€lls urat ut som saltkristaller (ofta natriumurat) +- Kristallerna lĂ€gger sig i leder, senor och omgivande vĂ€vnad (vanligast Ă€r stortĂ„ns grundled) och orsakar dĂ€r inflammation +- Vanligaste artritsjukdomen (uppskattad förekomst i Sverige, 1–2 % av befolkningen) +- De höga uratnivĂ„erna i blodet beror antingen pĂ„ ökad syntes eller pĂ„ minskad utsöndring av urat +- Beror oftast pĂ„ livsstilsfaktorer, lĂ€kemedelsbehandling eller annan sjukdom + +Preventiva Ă„tgĂ€rder inkluderar bland annat: + +- Minskat intag av alkohol. Vid metabolism av etanol bildas laktat som kompetitivt hĂ€mmar utsöndring av urat i tubuli +- Minskat intag av purinrika livsmedel (frĂ€mst inĂ€lvsmat, sardiner, ansjovis och musslor, men Ă€ven övrig fet fisk, skaldjur och kött) + +--- + +## LĂ€kemedelsbehandling av gikt – strategi 1 + +- HĂ€mma bildningen av urat genom att hĂ€mma enzymet xantinoxidas som ansvarar för sista steget i nedbrytningen av puriner +- Exempel pĂ„ lĂ€kemedelssubstanser som hĂ€mmar produktionen av urinsyra: + - Allopurinol (hypoxantinanalog) + - Febuxostat + +--- + +## LĂ€kemedelsbehandling av gikt – strategi 2 + +- HĂ€mma reabsorptionen av urat frĂ„n urinen i njurtubuli genom att inhibera urattransportörer (dessa Ă„terför normalt en stor del av utsöndrat urat till blodet) +- Ger sĂ€nkta uratnivĂ„er i blodet dĂ„ mer urat avgĂ„r med urinen +- Exempel pĂ„ substans: Probenecid + +--- + +## SvĂ„r kombinerad immunbrist (SCID) + +- SCID (Severe Combined Immunodeficiency) – samlingsnamn pĂ„ ett flertal ovanliga sjukdomar som beror pĂ„ avsaknad av immunceller som T- och B-lymfocyter, vilket leder till ett defekt immunsystem +- Utan behandling leder SCID till svĂ„r infektionsbenĂ€genhet och drabbade individer avlider ofta redan under det första levnadsĂ„ret +- Adenosindeaminasbrist; mycket ovanlig form av SCID i Sverige +- Autosomal recessiv nedĂ€rvning (mutationer i ADA-genen orsakar dysfunktionellt adenosindeaminas) +- En nĂ€rmast total brist pĂ„ immuncellerna T- och B-lymfocyter ses vid adenosindeaminasbrist + +--- + +## SvĂ„r kombinerad immunbrist (SCID) – till följd av adenosindeaminasbrist + +Möjlig koppling mellan enzymdefekt och avsaknad av immunceller: + +- Muterat adenosindeaminas som förlorat sin funktion → ansamling av deoxyadenosin som omvandlas till dATP → syntes av övriga deoxyribonukleotider hĂ€mmas (dATP hĂ€mmar ribonukleotidreduktas) → syntes, replikation och reparation av skadat DNA hĂ€mmas → pĂ„verkar framförallt snabbt prolifererande celler (celltyper med hög omsĂ€ttning) som dĂ„ genomgĂ„r apoptos (”programmerat sjĂ€lvmord”) +- T- och B-lymfocyter under utveckling Ă€r mycket snabbt prolifererande celler och tros dĂ€rför pĂ„verkas i speciellt hög grad av tillstĂ„ndet + +Behandling – gĂ„r ut pĂ„ att ge tillgĂ„ng till ”friskt enzym”: + +- Hematopoetisk stamcellstransplantation (benmĂ€rgstransplantation) frĂ„n frisk donator +- Enzymsubstitutionsbehandling, dvs enzymet ges som lĂ€kemedel (PEG-konjugat ADA injiceras subkutant) +- Genterapi; ”frisk ADA-gen” introduceras i individens egna hematopoetiska stamceller + +--- + +## Genterapi vid adenosindeaminasbrist + +- Har utförts pĂ„ ett fĂ„tal individer dĂ€r det inte varit möjligt att hitta lĂ€mplig donator + +Översikt: + +- Virus, med en frisk kopia av ADA-genen tillverkas +- De virus man anvĂ€nder saknar förmĂ„gan att ge upphov till sjukdom men har kvar egenskapen att bygga in nya gener i vĂ„r arvsmassa +- Virusen infekterar sedan hematopoetiska stamceller isolerade frĂ„n den sjuka individens benmĂ€rg och för pĂ„ sĂ„ sĂ€tt in den friska genen i dessa celler +- Cellerna ges tillbaka till den sjuka individen som dĂ€rmed har fĂ„tt ”friska stamceller” som kan bilda friska T-lymfocyter + +--- + +## Sammanfattning av nukleotidnedbrytning + +- Nukleotider har flera viktiga funktioner förutom att bilda nukleinsyrorna DNA och RNA +- Fem kvĂ€vebaser: + - TvĂ„ puriner; tvĂ„ ringar; GA + - Tre pyrimidiner; pyramid frĂ„n ovan; CUT + +- De novo syntes av nukleotider Ă€r dyrt vilket gör att baserna och sockerenheterna Ă„tervinns i hög grad + +Om fullstĂ€ndig nedbrytning av nukleotider: + +- Sockerdelen kan anvĂ€ndas direkt som energikĂ€lla (ATP) eller omvandlas till energirika produkter +- KvĂ€vebaserna: + - Puriner: URINSYRA (URAT) + mindre mĂ€ngd urea + - Pyrimidiner: UREA + energirika molekyler som kan anvĂ€ndas för direkt produktion av ATP eller omvandlas till energirika produkter + +- Defekter i nukleotidmetabolism kan orsaka sjukdom: + - Gikt; mycket vanlig artritsjukdom; uratkristaller i leder pga höga uratnivĂ„er i blodet + - Adenosindeaminasbrist (form av SCID); mycket ovanlig sjukdom; defekt adenosinnedbrytning orsakar nĂ€rmast total brist pĂ„ T- och B-lymfocyter; mycket infektionskĂ€nsliga + +--- + +## LĂ€sanvisningar + +- Detta förelĂ€sningsmaterial +- Biochemistry, 10th ed, Berg et al. + - 2023 W.H. Freeman, Macmillian Learning + - Kapitel 26: sidorna 809–810 + +- InstuderingsfrĂ„gor – finns upplagt pĂ„ Canvas + +Har ni nĂ„gra frĂ„gor? +Hör gĂ€rna av er till mig med ett meddelande pĂ„ Canvas + +**Nukleotidnedbrytning** \ No newline at end of file diff --git a/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/🗒 Anteckningar.md b/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/🗒 Anteckningar.md index e35c770..fca2e37 100644 --- a/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/🗒 Anteckningar.md +++ b/content/đŸ§Ș Biokemi/đŸ‹ïžâ€â™€ïž Metabolism/🧬 Nukleotidnedbrytning/🗒 Anteckningar.md @@ -6,3 +6,47 @@ tags: förelĂ€sare: Martin Lidell date: 2025-12-09 --- +Puriner: +- tvĂ„ ringar - tvĂ„ puriner + - adenin + - guanin + +Pyrimidiner: +- tre pyrimider, pyramid frĂ„n ovan + - cytosin + - uracil + - tymin + -![[Pasted image 20251209111439.png]] + + +Nukleotiders funktioner +- DNA/RNA byggstenar +- activatorer i biomolekyer och biosyntes +- byggstenar för CoA etc +- signalering + +Det Ă€r vĂ€ldigt dyrt för cellerna att bilda kvĂ€vebaser frĂ„n ingenting (de novo) +Om det gĂ„r att Ă„teranvĂ€nda redan uppbyggda kvĂ€ve baser, de utnyttjar man helst Ă„terigen. LĂ€nkar till en aktiverad form av ribos. + +Vi fĂ„r in mycket nukleiotider ifrĂ„n bĂ„de vĂ€xter och animaliska kĂ€llor + +I tarmens epitelceller kan man ta upp nukleosider, tas upp av cellerna och spjĂ€lkas ner till kvĂ€vebaserna. + +Nedbrytas: +- kvĂ€vebaser + - Ă„teranvĂ€ndning + - fortsatt nedbrytning + - urea + urate (puriner) + - hela kolskelettet kommer handla i urinsyra + - urea + energirika molekyeler (pyrimidiner) +- sockermolekyl + - Ă„teranvĂ€ndning + - energikĂ€lla + +Hur skapas uridsyra? +1. nukliotider konverteras till nukleosider +2. spjĂ€lkar bort aminogrupp (adenosin → inosine) +3. ribosen tas bort +4. hypoxantin +5. med hjĂ€lp av vatten tar bort en +