Protein

1- it starts in the stomach by the action of HCL that kills bacteria and activate pepsinogen into pepsin 2- pepsin digest protein into large polypeptides 3- entering small intestine , pancreatic proteases ( which are exopeptidases and endo ) eg : trypsin, chymotrypsin , elastases, collagenases Digest the large polypeptides into oligopeptides and free a.a 4- there is also enzymes called amino peptidases which are exopeptidases that cleave the N terminal of oligopeptides to make it even smaller and release a.a 5- free a.a are absorbed to enterocytes through sodium dependant secondary active transport via carrier called SLC and tri and bipeptides are also absorbed by proton linked peptide transporter and then hydrolyzed to a.a and all are transported to portal circulation then

It is amino acid plasma 1- it is not constant through 24h but it has a normal range between 4-8 mg/dl plasma 2- it contain a.a that is absorbed from diet , from hydrolysis of body protein , synthesised in body to form the pool finally

Anabolic fate - formation of protein : hormones, enzymes - formation of nitrogenous substances: purine , pyrimdine , glutathione Catabolic fate - cleavage of them into ammonia and carbon skeletons , ammonia is mostly converted to urea and excreted in urine , little ammonia is also excreted in urine, carbon skeletons are either glucogenic or ketogenic or both or maybe oxidized to co2 and water

The presence of a amino group keeps the acid away from being effected by oxiditive breakdown , the removal of the group make an obligatory step of oxidative breakdown

1- The first step in the catabolism of most amino acids is the transfer of their a-amino group to a- ketoglutarate, producing an a-keto acid (derived from the original amino acid and glutamate ) a-ketoglutarate accepts a amino groups and is converted to glutamate That can be oxidatively deaminated or used as amino group donor This process is catalyzt by enzymes named transaminases or aminotransferases that uses PLP as co enzyme There areTwo important transaminases reactions , one catalyzd by alanine aminotransferase ( ALT) and aspartate aminotransferase ( ACT)

Their reactions are reversible however during catabolism direction of the reactions goes to glutamate synthesis ( alanine breakdown )

Libration of a amino group from glutamate forming a ketoglutarate and ammonia which converts to urea and excreted and this process is done by glutamate dehydrogenase in liver and kidney mainly ,

1- unique as the glutamate is the only a.a to be oxidatively deaminated 2- it is mitochondrial enzyme 3- a keto glutarate ~> glutamate ( NADPH/ NADP) Glutamate ~> a ketoglutarate ( NAD/ NADH) 4- Allostericly inhibited by guonseine triphosphate and activated by ADP ( low level of energy)

1- glucogenic Their catabolism gives arise to intermediates of TCA cycle that can undergo gluconeogensis and give glucose 2- ketogenic Their catabolism gives arise to acetoacetate or any precursor of ketogenisis ( acetyl coa or acetoacetyl coa) to give ketone bodies There are two : leusine and lysine 3- both Their carbon skeleton after deamination gives arise to glucose and ketone bodies , they are tyrosine , tryptophan, phenylalanine and isoleucine

1- glucogenic as it can convert to serine by serine hydroxymethyl transferase and then serine converts to pyruvaic acid by serine dehydratase 2- its non essential a.a

1- serine synthesis 2- pyrine synthesis Carbon no . 4,5 and nitrogen no .7 derivatives from glycine 3- creatine synthesis As it consists if 3 a.a ( glycine, arginine, methionine) 4- heme formation As glycine reacts with succinyl CoA giving aminoleuvlinc acid ( ALA) that later convert to heme 5- glycine betiane : methyl donor 6- bile salt formation : glycine is conjugated with bile acids to give bile salts that help in emulsification of fat 7- glutathione synthesis That is formed from glycine, cysteine and glutamate

There is two forms oxidized ( GS SG) and reduced ( GSH ) Cysteine and glutamate get together by cysteinyl glutamate synthatase and then glycine is added to form glutathione by glutathione synthatase It has important roles as 1- a.a transporter through mucosal membrane ( glytamyl cycle ) 2- antioxidant ( mentioned before) 3- GSH as cofactor in many processes like PGs synthesis and Aconitase in TCA cycle 4- detoxification of arommatic compounds like bromobenzenes

Nitrogen intake and output or can be protein anabolism and catabolism as most nitrogen intake are in protein and most of nitrogen output results from protein breakdown

Normally there is balance between nitrogen intake and output , it occurs in normal healthy adults + : intake > output and this happens during synthesis of new tissues as in growth and pregnancy and during musclar training - : output > intake it can be due to Loss of protein eg chronic haemorrhage Increased protein Catabolism eg DM little protein intake eg starvation

• Phenylalanine is an essential amino acid. • Tyrosine is a non-essential amino acid, as it is synthesized from phenylalanine by hydroxylation. This reaction is catalyzed by phenylalanine hydroxylase and BH4 as coenzyme ( tetrahydrobiopterin) that is converted to BH2 ( dihydrobiopterin) in the end and is regenerated by dihydrobiopterin reductase that needs NADPH+H or NADH and any deficiency in these substances hencing phenylalaline to convert to tyrosine results in PKU

Tyrosine is a ketogenic and glucogenic . The catabolic products are fumarate (glucogenic) and acetoacetate ( ketogenic)

Catecholamine Synthesis: Tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA) DOPA is decarboxylated to dopamine that undergoes hydroxylation to norepinephrine (noradrenaline). Methylation of norepinephrine results in formation of epinephrine (adrenaline). Melanin synthesis Melanin is a dark brown pigment present mainly in skin, hair giving them their colors. Melanins are synthesized to protect underlying cells from the harmful effects of sunlight Thyroid hormone synthesis

Phenylketonuria (PKU), is one of the most common inborn errors of amino acid metabolism (prevalence 1:15000) • Causes 1. Most of the cases of PKU are due to the deficiency of phenylalanine hydroxylase (Classic PKU). Deficiency of PAH will lead to the accumulation of phenylalanine. 2.1 - 2% of PKU cases are due to deficiency of tetrahydrobiopterin (BH4)which is the coenzyme for phenylalanine Signs and symptoms Failure to walk and talk Hyperactivity and tremors Failure to grow Increased blood phenylalanine : part of it is excreted in urine and part is converted to phenyl pyruvate and phenyl lactate that go to BBB and compete with other substances important for brain and entering as they have higher conc. leading to mental retardation Neonatal screening and diagnosis of PKU Early diagnosis of PKU is important because the disease is treatable . Because of the lack of neonatal symptoms, laboratory testing for elevat-ed levels of phenylalanine is essential for the diagnosis. And its applied in many countries Treatment The treatment of classic PKU consists of dietary restriction of phenylalanine with tyrosine It must continue for at least eight years. It’s better to be lifelong. Treatment must begin during the first seven to ten days of life to prevent mental retardation.

SYNTHESIS Tryptophan is an essential amino acid. CATABOLIC FATE • Tryptophan is a mixed amino acid (both glucogenic and ketogenic). Glucogenic as it gives alanine that is transaminated to give pyruvate Ketogenic as it gives acetoacetyl CoA

Pyridoxine is important to the intermediary steps of tryptophan catabolism. Its deficiency impairs formation of nicotinic acid from tryptophan, and a sec-ondary metabolite (xanthurenic acid), instead, is formed and excreted in urine

Nicotinic acid: It is used for synthesis of NAD+ and NADP+. • Formyl THE: 3-Serotonin: Serotonin is 5-hydroxytryptamine. Tryptophan undergoes hydroxylation and decarboxylation to form serotonin 4- melatonin

Serotonin is synthesized in the nervous tissue and in the intestine It is an important chemical transmitter in the CNS vasoconstrictor. • CARCINOID TUMOR This tumor presents with increased levels of serotonin and its metabolite: 5- hydroxyindole-acetic acid (5-HIAA) in both blood and urine. 5-HIAA is formed by oxidative deamination of serotonin by monoamine Oxidase (MAO). Pellagra may develop in carcinoid tumor because tryptophan metabolism is shunted towards synthesis of serotonin by the tumor cells and 5- hydroxyindole-acetic acid

Serotonin is acetylated to N-acetyl serotonin that is methylated to melatonin • Melatonin acts as antioxidant. promoting sleeping to some extent. It acts as an antidepressant. Neurotransmitter

Pellagra like manifestations