One Carbon Transfer Groups

• Tetrahydrofolate FH4
• Vitamin B12 or cobalamin
• S-adenoylmethionine(SAM)

Absorption of Tetrahydrofolate

• folate is esential vitamin absorbed by proton coupled folate transport(PCFT) SLC46A1 or reduced carrier transported SLC19A1 (SLC=Solute ligand carrier)
• loss of PCFT of proximal thid of intestine results in anemia and diarrhea
• folate is taken up by liver through portal vein and reconjugated with glutamate 
• folate is reduced to tetrahydrofolate by dihydrofolate reductase 
• N5-methyl FH4 is major blood folate transported to other tissue bound to albumin

Oxidation and reduced form 

of Tetrahydrofolate

• FH4 recieves one carbon from either(tryptophan, histidine, serine, glycine) 
• involved in purine syntheses, dTMP syn and methylated VB12, and connects folate cycle to methione cycle
• tryptophan donates formate group for purine synthesis
• histidine donates formiminoglutamate group, closing the ring, to form an intermediate product
• methylene tetrahydofolate reductase converts the intermediate to a methylene group to be used for dUMP to dTTP 
• glycine and serine give methylene group for methylene tetrahydrofolate reductase to form VB12

Recipients of FH4 Carbons

• serine hydroxymethltransferase(major source of one carb groups in humans
• Thymidylate synthase
• methylene FH4 reductase
• methionine synthase
• dihydrofolate reductase
• glycine cleavage enzyme
• histidase release NH4 +
• kynurenine formamidase
• transformylase

Absorption of VB12(cobalamin)

• free B12 bound to haptocorrins or transcobalamin I secreted by salivary glands and stomach mucosa
• pancreatic protease digests these and B12 binds to intrinsic factor 
• Small intestine illium has intrinsic factor receptors
• B12 binds to transcobalamin II in enterocyte
• 50% of B12 is stored in liver
• failure to absorb b12 caused by deficiency of IF causes pernicious anemia

Reactions Requiring VB12(Cobalamin)

• recieves methyl group from N5-methyl folate so linked to folate metabolism
• involved in 2 reactions
• conversion of homocysteine to methionine by methionine synthase(prevents homocystinemia associated with CardioVas disease and neurological)
• use of propionyl-CoA to form methlmalonyl CoA that is converted to succinyl CoA by methylmalonyl CoA mutase
• notice both pathways produce succinyl CoA

S-Adenosylmethionine (SAM)

• Methionine adenosyltransferase(MAT) is the rate limiting enzyme in the synthesis of SAM
• SAM can then transfer its methyl group in numerour rx by the action of specific methyltransferase enzymes
• this results in formation of S-adenosylhomocysteine(SAH)
• Adenosylhomocysteine is cleaved by adenosylhomocysteine hydrolase(AHCY) to form homocysteine
• homocysteine is converted to ietihonine by methionine synthase and cofactor VB12

(SAM) Methyltransferase reactions

• specific methyltransferase enzymes for conversion of each
• epinephrine for lipolysis
• creatine for muscle energy (glycine+ arginine then transport to liver for SAM reaction)
• methylated nucleotides of RNA, DNA genomic imprinting, mother daughter strand recognition, gene expression
• phosphatidylcholine in VLDL synthesis and transport
• melatonin sleep-wake cycle (seratonin to melatonin)
• DNA nucleotide methyltransferases being targeted for cancer treatment

Polyamines 

• polyamines are cations that help package DNA into nucleoids (condense euchromatin to heterochromatin) 
• SAM functions in the synthesis of them 
• most important polyamine are spermidine and spermine
• SAM is decarboxylated and the propylamine groups of SAM is transferred by specific polyamine synthase to form spermidine and spermine

Transulfation Pathway

• homocysteine is the demthylation product of SAM
• homocystine is converted to cysteine by cystathionine synthase and then cystathionase
• cysteine is an important source for the synthesis of Glutathione(GSH)

Hyperhomocysteinemia

• caused by cystathionine synthase deficiency(converts to cystathionine)
• no mechanism found that links the elevated levels to pathological changes
• homocysteine cause LDL to aggregate and taken up by macrophages
• homocysteine can cause lipid peroxidation and platelet aggregation
• homocysteine is converted to methionine by methionine synthase and betaine methyltransferase (only exists in liver)

Methionine Synthase

• converts homocysteine to methionine 
• requires both methyl donors B12 and folate to convert homocysteine
• neural tube defect are due to variant of methylene tetrahydrofolate reductase resulting in homocystinuria

Betaine in liver

• can be used as a methyl group donor to homocysteine reaction to methionine in the liver
• the liver contains the enzyme betaine methyltransferase that is not found anywhere else
• liver also contains methionine synthase(uses FH4 and B12) so it can conduct two pathways 

Plasma Proteins of Clinical Significance

(transport)

• thyroxine binding globulin(thyroid hormones)
• apolipoproteins(cholesterol, TG)
• transferrin(iron)

Plasma Proteins of Clinical Significance

• HI: immunoglobulins
• Oncotic pressure: albumin, proteins

Plasma Proteins of Clinical Significance

• enzymes: renin, coagulation factors, complement proteins
• protease inhibitors: α1-antitrypsin (decreases with smoking)

Liver Cirrhosis

(plasma proteins)

• albumin decreases withile α2 increase and y-globuline increase

Nephrotic Syndrome

(plasma proteins)

• protein losing condition
• loss of albumin and y-globulin with increase in αglobulin (due to α2macroglobulin)(immunoglobulins)
• damage to glomerular basement membrane-podocytes low molecule protein loss

Monoclonal gammopathy

(plasma proteins)

• seen in cancers
• decrease albumin with increase y-globulin (immunoglobulins)

Acute-Phase Proteins

• levels change w/i 1-2 days after surgery, infection and inflammation
• synthesis in liver is controlled by ctokines and stress hormones
• albumin peak is reduced while α2-globulin fraction increases mainly due to haptoglobulin(binds Hb)
• C-reactive protein increases 100fold after bacterial infection
• Y-globulin fraction increases in chronic disease infection, malignancies and liver cirrhosis

Liver Function Tests

• blood urea nitrogen
• albumin cocentration
• plasma protein synthesis
• bilirubin
• prothrombin time in coagulation

Causes of unconjugated hyperbilirubinemia

• hemolysis
• Gilberts syndrome: decreased expresssion of UDP-glucuronyl transferase (transports glucuonyl to bilirubin)
• Crigler-Najjar: total absence of UDP-glucuronyl transferase (no conjugated bilirubin)
• Dublin-Johnson: due to decreased hepatic excretion of bilirubin because of defective ABC transporter[Organic Anion Transporter(OAT)], leading to increase urinary bilirubin excretion

Albumin and osmotic pressure

• determines 90% of coloidal osmotic pressure
• has half life of 17 days present in plasma and IF and lymp but at lower conc than in plasma
• colloidal osmotic pressure is necessary to prevent edema(happens when albumin drops below 2g/dl
• other cause of edema include increase cap permeability, venous obstruction, impaired lymph flow, congestive heart failure

Hyponatremia and hypernatremia

• hypo: lower than normal (< 135 mmol/L) concentration of sodium in serum
• hyper: higher than normal concentration of sodium in serum 

Anion Gap

• useful for identifying an increase in 1 or more unmeasured anions ins erum usually ketone bodies, acetoacetate
• causes of elevation: uremia/renal failure, ketoacidosis, glycol poisoning, lactic acidosis

5 isozymes of Lactate Dehase(LDH)

• H(heart) and M(muslce) monomers
• most tissues convert pyruvate to lactate while liver(M4) converts lactate to pyruvate
• if heart form is up then myocardial infarction
• if m4 then liver failure

Isozymes of Creatine Kinase

• CK-1 BB in brain
• CK-2 HM in myocardium
• CK-3 MM in skeletal muscle

Microsomal Transfer Protein

(MTTP)

• enzyme only found in liver
• condesnes ApoB100 with phospholipids and cholesterol 
• can account of elevated VLDL triglycerides

Fructose Consumption

• preferentially taken up by liver
• uptake is not regulated by insulin
• increases lipogenesis
• depletes the liver of inorganic phosphates
• reduces oxidative phosphorylation

BCAA transaminase

• converts valine, isoleucine, or leucine to a αketoacid
• deficiency of this enzyme leads to maple syrup urine 
• cofactor most likely Vitamin B6 (pyridoxal phosphate)

Cortisol in Kidney vs Liver

• cortisol in the kidney stimulates glutaminase which converts glutamine to NH3
• cortisol in the liver stimulates glutamine synthase that synthesizes glutamine (upregulated by H, or glucocorticoids) 

Refsum's Disease

• defect in α-oxidation
• alpha is used in odd chain and long branched chain FA oxidation 
• leads to accumulation of branch chained Fatty acids that lead to neuroligical problems in infants

Cholchicine

• used in treatment of intercritial(middle), sub acute phase of gout
• this phase is around day 10
• decreases inflamatory response due to swelling and pain
• inhibits tubulin synthesis in WBCs (prevents phagocytic activity)
• can cause diarrhea

Describe 3 causes of hyperuracemia

• increased production(overproduction): tumor lysis syndrom or Lesch-Nyhan syndrome
• decreased excretion(underexcretion): drugs(diuretics, salicylates), lead toxicity 
• Mixed: ethanol and starvation, high fructose diet

Describe 3 biochemical mechanisms and associated 

clinical scenarios involved in gout

• High NADH/NAD ratio shifting LDH rx to lactate(ethanol)
• HGPRT enzyme deficiency (lesch-Nyhan)
• increased purine substrate converted to UA: starvation or high purine diet

Describe 3 Clinical Phases of Gout

• Acute: use antyinflamatory or Steroids 
• Subacute: use colchincine, WBC membrane stabilization, inhibit tubulin synthesis
• Chronic: decrease formation(allopurinol, febuxostat), increase removal(Urate oxidases to allontoin that is more soluble), decrease absorption of UA

Tangier's Disease

• yellow tounge, yellow rectal mucosa with orange-brown spots, hepatomegaly and splenomegaly 
• autosomal codominant ABC1 mutation
• double deletion mutation results in a frameshift and early termination in ABC1 
• low lipoproteins, premature atherosclerosis
• tangier's disease has low ApoA1 but no ApoA1 mutation(mutation is in transport to apoproteins)(it becomes degraded because it never forms with HDL) 
• with out mature form of HDL, mature VLDL and chylomicrons are not formed
• chylomicron levels can be increased in these patients(all other lipoprotein levels low)

HDL₂ and HDL₃ 

• HDL2 is larger(TG), less dense and more protective against Coronary heart disease
• HDL3 smaller, dense and less protective
• HDL2 seems to be one that goes back to liver(active)