Metabolism of sulfur amino acids

3rd Patient-Expert Meeting, Rome, 2019

Viktor Kožich

Department of Pediatrics and Adolescent Medicine

Charles University-First Faculty of Medicine and General University Hospital

Prague, Czech Republic

Outline

Sulfur amino acids and related compounds• Amino acids and their metabolism• Methionine• Homocysteine• Homocysteine, homocystine or total homocysteine?• Cysteine• Hydrogen sulfide• Daily intake of SAA

Metabolism of SAA• Sulfur cycle in Nature• Methylation• Transsulfuration• Conversions of cysteine

Amino acids

• Building blocks of allproteins in the body (about20,000 different proteins)

• Proteins enable allfunctions in the body• Structure• Enzymatic reaction• Energy production• Regulation• Many other

• AA are precursors of important chemicals (non-protein small moleculemetabolites)

http://uk.geocities.com/david.bender@btinternet.com/images/proteinoverview.png

~ 400 g

Methionine

• Essential amino acid

• Present in proteins

• Donor of methyl group• Dozens of reactions

• Creatine in muscles and carnitine

• Neurotransmitters

• DNA methylation

• Plasma concentration 15-40 µmol/L

Homocysteine

• Non-essential amino acid

• Not present in proteins

• Formed in the body frommethionine

• Normal metabolism• Remethylation back to Met• Production of Cys

• Plasma concentration tHcy 5-15 µmol/L

• Abnormally high Hcy• Multiple effects• Adverse effects on vasculature• Implicated in neurological diseaseCH3

Homocysteine, homocystine, tHcy

Homocysteine Homocystine

Protein boundhomocysteine

Total Hcy

Blood

Cysteine

• Semiessential (essential forgrowth, may be formed fromMet)

• Contained in proteins, formsdisulfide bridges (tertiarystructure of proteins)

• Precursor of importantmolecules• Glutathione• Taurine• Hydrogen sulfide

• Plasma concentration (tCys)250-350 µmol/L

Hydrogen sulfide• Different sources of hydrogen

sulfide• Used early in Life in

archaebacteria for energyproduction

• Physiological functions• Vasodilation• Neurotransmission• Immunomodulation

• End-product of H2S catabolism issulfate

• Plasma concentrations• H2S < 0.2-0.5 µmol/L• Sulfate 300-500 µmol/L

Hydrogen sulfide

Hcy Cys

Gut microbiota

Endogenoussynthesis

FoodGarlic, onionCruciferous veggies

Recommended daily intake Met+Cys

• WHO: 10.4 + 4.1 (15 total) mg per kg body weight, i.e. 1050 mg total per 70 kg

• US : total 19 mg per kg body weight

• The recommended daily intakes for children aged three years and older is 10% to 20% higher than adult levels

• For infants can be as much as 150% higher in the first year of life. Cysteine (or sulfur-containing amino acids) …. are always required by infants and growing children

Cystine 1.04 (1.00, 1.08)

0.94 (0.91, 0.97)

0.88 (0.85, 0.91)

0.84 (0.81, 0.87)

Methionine 1.67 (1.60, 1.74)

1.38 (1.33, 1.43)

1.24 (1.20, 1.29)

0.88 (0.84, 0.92)

Meat-eaters Fish-eaters Vegetarians Vegans

(n=98) (n=98) (n=98) (n=98)

Age years 44 (37, 44) 41 (36, 45) 43 (36, 44) 40 (35, 44)

Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and

vegans: a cross-sectional analysis in the EPIC-Oxford cohort. Eur J Clin Nutr. 2016 Mar; 70(3): 306–312

Table 3 Intakes of amino acids by habitual diet group (median, men)

Estimatemg/kg/d

#39 33 30 24

How much sulfur AA do we eat?

#Assuming 70 kg body weight

Outline

Sulfur amino acids and related compounds• Amino acids and their metabolism• Methionine• Homocysteine• Homocysteine, homocystine or total homocysteine?• Cysteine• Hydrogen sulfide• Daily intake of SAA

Metabolism of SAA• Sulfur cycle in Nature• Methylation• Transsulfuration• Conversions of cysteine

Sulfur cycle in Nature-animals

Met

Hcy

Cys

Methylatedproduct

SulfateInorganic sulfur

Methyl groupdonors(+ folates + vitamin B12)

Lecture Prof.Henk Blom

Sulfur cycle in Nature-plants

Met

Hcy

Cys

SulfateInorganic sulfur

(Trans)methylation

1. S-adenosylmethionine(AdoMet) synthesis

• S-adenosylmethionine is themethyl group donor

2. Transfer of methyl groupreleases S-adenosyl-homocysteine (AdoHcy)

3. Hydrolysis of SAH to homocysteine and adenosine by AHCY

Methylatedproduct

Transsulfuration

• Irreversible reactions in sulfur amino acid metabolism

• Both enzymatic reactionrequire PLP (drived fromvitamin B6)

• CBS mostly expressed in liver, pancreas and kidney

• CTH expressed in many tisues

• Promiscuity of CBS and CTH towards substrates

Hcy

Cys

Alternative TS reactions (H2S synthesis)

Canonical reactions Alternative reactions

Conversions of cysteine

• Cys molecule preserved in GSH, -SH group necessaryfor oxidoreduction reactions

• Oxidation by CDO to cysteinesulfinate (via hypotaurine to Tau or via sulfinylpyruvate to sulfite)

• H2S oxidized in mitochondriavia SQR, PDO and SUOX (with generation of reducedequivalents for respiratorychain)

Cysteine

Glutathione Taurine

Inorganiccompounds

Sulfur bound to carbon

Summary

• Sulfur cycle in Nature-humans only catabolize sulfur

• Met essential, Cys semiessential amino acid

• Recomended daily intake Met+Cys 15-19 mg/kg/d in adults (higher in infants and children)

• Hcy is at intersection of pathways

• Sulfur metabolism produces important compounds

• End-product of sulfur metabolism is sulfate