number Done by Corrected by Doctor Dr.Diala

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1 number 32 Done by Mousa Salah Corrected by Bahaa Najjar Doctor Dr.Diala 1 P a g e

2 In the last lecture we talked about the common processes between all amino acids which are: transamination, deamination, urea cycle (which happens to the ammonia) and at the end (when the ammonia is removed) we will end up with α-keto acid. In this lecture we will talk about the next section of amino acid metabolism and the processes of amino acids degradation. Every amino acid has a different carbon skeleton, every one acts differently in the degradation process, so we deal with each amino acid differently and everyone will give different products. Classification of amino acids If we want to study amino acids and understand the degradation processes to each one of them we have to classify them according to the final product of their carbon skeleton metabolism, there are 7 final products that are produced from the 20 amino acids, so we classify them into:- 1- Glucogenic : most amino acids are glucogenic, their final products can be used in gluconeogenesis, these are the amino acids that neither ketogenic nor both (ketogenic and glucogenic) catabolism yields pyruvate or one of the TCA cycle intermediates that can be used as substrates for gluconeogenesis in the liver and kidney" 2- Ketogenic:leucine and lysine(both start with L ), they are essential amino acids, their final products can be used to produce ketone bodies catabolism yields either aceto acetate (a type of ketone bodies) or one of its precursors (acetyl CoA or acetoacetyl CoA). Other ketone bodies are" 3- Both glucogenic and ketogenic: they have more than one final product that they can be either ketogenic or glucogenic, these amino acids are tyrosine, isoleucine, phenylalanine and tryptophan, all of them are essential amino acids except tyrosine, and all of them have benzene ring except isoleucine. 2 P a g e

3 *Some amino acids have the same final product for example, more than one amino acid will give pyruvate or acetyl coa. Degradation of amino acids We will study the amino acids metabolism in groups, one by one according to their final products: - Amino acids that produce oxaloacetate 1- Aspartate: the process of transamination of aspartate converts it to oxaloacetate by the action of the enzyme aminotransferase, which transfer the amino group to α-ketoglutarate to produce glutamate. So oxaloacetate produced by a very simple process (transamination reaction), single step metabolic pathway. 2- Asparagine: asparagine is very related in its structure to aspartate, the difference between them is only the amine group. So the first step in asparagine metabolism is to remove the amino group to convert it to aspartate by the enzyme asparaginase, then aspartate will enter the transamination reaction to produce oxaloacetate. *so asparagine and aspartate are amino acids that produce oxaloacetate, which is a kreps cycle intermediate, so it can activate the process of gluconeogenesis. - Amino acids that produce α-ketoglutarate via glutamate 1- Glutamate: α-ketoglutarate is produced by a deamination reaction (removal of amino group) "by the enzyme glutamate dehydrogenase" 2- Glutamine : we start its metabolism by removing the amine group to have glutamate (just like asparagine), then the deamination reaction occurs by the enzyme glutamate dehydrogenase so we will end up with α-ketoglutarate. 3 P a g e

4 3- Proline: different in structure with glutamate and glutamine, but it gets oxidized to glutamate to produce α-ketoglutarate. 4- Arginine: the first part in arginine metabolism is producing ornithine by removing the urea from it (in urea cycle), after that the ornithine is going to be converted to α-ketoglutarate via glutamate. 5- Histidine: it is a common amino acid that have a ring in its R group, the first step in histidine metabolism is removing the amine group by the enzyme histidase so we will end up withurocanic acid (the ring+ COO- +2 carbons with double bond between them). In order to be able to produce α-ketoglutarate we have to open the ring s structure, urocanic acid will pass through a cascade of steps and after some reactions the ring structure will be opened producing N-formimino-glutamate, we can tell from this name that this compound is similar in its structure to glutamate, the only difference is the formimino group (a carbon and a nitrogen connected by a double bond). The next step is removing the formimino group so N-formimino-glutamate will be converted to glutamate which will be converted to α-ketoglutarate. In our body, there are a lot of reactions that require transferring single carbon units (formimino, formyl and methyl) to other molecules, so in this reaction,formimino will be transferred by tetrahydrofolate (the active form of folic acid, vitamin B9) which will be converted to 5-formimino-tetrahydrofolate,so at the end N-formimino-glutamate will be converted to glutamate. - Amino acids that produce pyruvate 1- Alanine: alanine gets degraded by transamination reaction, so alanine aminotransferase removes the amine group and gives us the pyruvate. 2- Glycine: there are two ways to metabolize it :- 4 P a g e

5 It may enter an oxidation reaction directly, because of its very simple structure Glycine oxidation CO2 + NH3 It can be used to produce serine (different from glycine in one carbon and OH group), so we need to transfer to glycine one carbon (which is done by tetrahydrofolate) and also we need a hydroxyl group to be added, by the action of serine hydroxymethyltransferase glycine will be converted to serine. 3- Serine: after serine is produced from glycine, we convert it to pyruvate by removing from it H2O molecule and amine group by the enzyme serine dehydratase. 4- Threonine: related in structure to serine, have OH group, it can be converted to pyruvate (like serine), or it can be converted to α-ketobutarate which is at the end becomes succinylcoa, so threonine can produce more than one product (pyruvate and succinylcoa) 5- Cystine: related in structure to serine but instead of hydroxyl group (OH), it has thiol group (SH). The metabolism process starts with a reduction reaction by the action of the enzyme cystine reductase to produce cysteine, cysteine then proceeds just like serine metabolism to produce pyruvate. *Note that cystine is different than cysteine, cystine has disulfide bridge and it is reduced to cysteine. - Amino acids that produce fumarate Phenylalanine and tyrosine: both have benzene, tyrosine have OH group in addition to benzene. We start the metabolism process by producing tyrosine, which is done by adding hydroxyl group (OH) to phenylalanine by the enzyme phenylalanine hydroxylase, then tyrosine gets metabolized and we end up with two products:- 1- Fumarate 5 P a g e

6 2- Acetoacetate: one of the ketone bodies *from the products we can conclude that these amino acids are both glucogenic and ketogenic. Application on phenylalanine/tyrosine metabolism Phenylalanine and tyrosine metabolism is done by a lot of enzymes, genetic problem may occur in these enzymes, these genetic problems will lead to some diseases in our bodies, the following are examples on these genetic diseases: Phenylalanine hydroxylase deficiency will lead to phenylketonuria (PKU). Tyrosine enters in producing a lot of nitrogen containing compounds in our bodies, the most important one of these compounds is melanin pigment that exists in skin, hair and eyes. Problems in metabolism of tyrosine will lead to albinism (the color of the skin and hair will be very light). - Amino acids that produce succinylcoa 1- Threonine: we have discussed it in amino acids that produce pyruvate. 2- Valine and isoleucine: branched chain amino acids, means the branching starts directly on the beginning of the R group, in other words it starts to get bulky directly on the α-carbon so there is no long chain. Later we will discuss these amino acids in details because of their importance. 3- Methionine: considered as one of the most important amino acids because it enters in the process of protein synthesis, whereas the initiation of amino acids sequence is always methionine no matter what the protein or the sequence is. The metabolism of methionine starts by the action of the enzyme S-adenosylmethionine synthase to produce S-adenosylmethionine (SAM), this reaction is adding adenosine group which comes from ATP to the sulfur in methionine. 6 P a g e

7 SAM has an importance which is working like tetrahydrofolate in transferring single carbon units, so SAM works as methyl donor which is giving single carbon unit in the form of methyl group to another compounds methyl acceptors, so we can use SAM in methylation reactions because it carries methyl group which can donate/give very easily. So the peripheral methyl group on the sulfur atom in SAM will be transferred to another molecules (methyl acceptors) and what remain from SAM is S-adenosylhomocysteine (SAH), this compound looks like cysteine because the sulfur isn t between to carbons like methionine, it becomes peripheral in position. The next step is removing the adenosine group to produce homocysteine. Homocysteine is considered an important intermediate in this metabolism process, because it is a point of branching in this pathway, in other words in this point the pathway proceeds in one of two ways, either way is chosen according to the body s demand or which enzymes or cofactors are present. The two ways are:- Either homocysteine is used in the production of cysteine (using methionine to produce cysteine), which will enter in a conjugation reaction, this reaction is connecting homocysteine with parts from serine (will be converted to H2O) by the enzyme cystathionine β-synthase to produce cystathionine, vitamin B6 is a cofactor in this reaction. Or it can go back and produce methionine again,homocysteine will be converted back into methionine by the action of methionine synthase,n5-methyl-tetrahydrofolate enters the reaction as a methyl donor which will give the methyl group that is connected on nitrogen 5 to homocysteine to produce methionine and after losing the methyl it will return back to tetrahydrofolate. Vitamin B12 is present in this reaction as a cofactor (cannot work without tetrahydrofolate). 7 P a g e

8 *There are a lot of studies that have been conducted on homocysteine and the diseases that are related to it, for example the cardiovascular diseases (CVDs) which has been found that people with CVDs have an increased level of homocysteine. Homocysteine starts to accumulate due to many reasons, the most important ones are:- Deficiency in cystathionine β-synthase which converts homocysteine to cystathionine, so this will stop cysteine synthesis/production. Homocysteine enters in cysteine or methionine production, the presence of cofactors like vitamins B6, B9 and B12 is crucial, deficiencies in these vitamins will cause problems, these deficiencies are prevalent in our community. It is difficult to have Vitamin B9 or folic acid deficiency in our community because we eat it not by our choice, it is added to a lot of food products like bread and flour, we call this.(تدعيم الطعام) process of adding folic to the food products, food fortification So we use food fortification especially for folic acid so that we don t end up with folic acid deficiencies especially in pregnant women, deficiency in folic acid during pregnancy may cause in the baby birth defects, the most important one is spina bifida (bones of spine/vertebrae don t form properly around part of the baby s spinal cord), it can be treated but its treatment cost much more than preventing it with food fortification. Folic acid fortification is a controversial subject because of many reasons:- Women in particular are subjected to huge amounts of folic acid, theytake it before pregnancy (planning to get pregnant) for 3 months, and also after pregnancy they take it for 3 months, which means in every pregnancy women take folic acid for 6 8 P a g e

9 months plus the folic acid that comes from our original/natural food like leafs, plus the folic acid that comes from grain products like bread and flour. In our community there are deficiencies (mutations) in the enzymes that metabolize folic acid, so if a person is given folic acid (inactive form) and he doesn t have enzymes that can metabolize it, this condition is now questionable, especially that many researches have been conducted on our community and other communities, these researches connect between these mutations and some types of cancers (the most common ones like breast, lung ), this has not been proved but it has been found that people with these mutations (deficiencies) have a higher percentage of having cancer than the normal people. So many people in our community have shown a great interest in folic acid fortification and its connection with cancer, especially that cancer patients are increasing, for example between every 3 women there is one with breast cancer. - Amino acids that produce acetyl coa / acetoacetate They are ketogenic or both ketogenic and glucoginec 1- Leucine: branched chain amino acid, exclusively ketogenic and produce acetyl coa and acetoacetate. 2- Isoleucine: branched chain amino acid, produce acetyl coa and succinylcoa, so it s both ketogenic and glucogenic. 3- Lysine: exclusively ketogenic, produce acetoacetylcoa. 4- Tryptophan: contains benzene ring, produce acetoacetylcoa and alanine (which is converted to pyruvate), so tryptophan is both ketogenic and glucogenic. Catabolism of branched chain amino acids (valine, leucine, isoleucine) The catabolism of branched chain amino acids is different from other amino acids in two things:- 1- This catabolism process happens particularly in muscles, not in the liver like the other amino acids. 2- These amino acids share a different way of metabolism. 9 P a g e

10 The catabolism process occurs in this sequence :- - Transamination: just like all amino acids, this reaction needs vitamin B6. - Oxidative decarboxylation: in this reaction a carboxyl group (COO-) is removed, some coenzymes are needed like FAD, NAD+ and coa. - Dehydration: α-β-unsaturated acyl coa will be produced. - At the end we will have the final products Valine (glucogenic) SuccinylcoA Leucine (ketogenic) acetoacetate, acetyl coa Isoleucine (both) SuccinylcoA, acetyl coa *we will not be asked about the intermediates, just the reactions and the final products Role of folic acid in amino acid metabolism Folic acid exists in the inactive form (folate and folic acid), we use it as we mentioned before in the fortification processes. In order folic acid to be used by the body or to be recognized that it can be loaded by single carbon units, it has to be converted to its active form which is tetrahydrofolate, so folic acid enters a reduction reaction (4 hydrogen atoms are added) in order to be converted to tetrahydrofolate. Tetrahydrofolate can load single carbon unit in different forms, which are:- *single carbon unit is loaded on nitrogen 5 or 10 in tetrahydrofolate, and sometimes it (carbon unit) is connected on both nitrogen 5 and 10 at the same time. - Formyl (C=O), it is added on nitrogen 10 so tetrahydrofolate will be converted to N10-formyltetrahydrofolate, this is used specifically in the process of purine synthesis. - Methenyl: the second e means there is a double bond in the molecule, so basically we remove the oxygen atom in the formyl and we connect the rest (which is methenyl) with tetrahydrofolate in nitrogen 5 from one side with single bond and in nitrogen 10 from the other side with double bond, so tetrahydrofolatewill become N5,N10-methenyl-tetrahydrofolate. 10 P a g e

11 - Methylene: doesn t connect with tetrahydrofolate by double bond, so basically methylene is CH2 that connected from two sides by single bonds, so methylene connects to tetrahydrofolate on nitrogen 5 and 10 by single bonds and become N5,N10-methylene-tetrahydrofolate. *This enters in the production of the nucleotide Thymine (T) which is present only in DNA while the complementary nucleotide in RNA is Uracil (U), the difference between them in structure is one methyl group (CH3), so N5,N10-methylene-tetrahydrofolate is used in adding the methyl group to uracil (U) to produce thymine (T). - Methyl : methyl group is added to nitrogen 5 to produce N5-methyl-tetrahydrofolate, it is used in the metabolism process of methionine, so when methionine is converted to homocysteine and it is used to produce methionine again, we use N5-methyl-tetrahydrofolate and Vitamin B12 is needed in this reaction. *In our society we have a problem in this compound (N5-methyl- tetrahydrofolate), more than 24% of the Jordanian population have a mutation (deficiency)in the enzyme that produce this compound, and the percentage goes higher in the minorities like the Chechnya (30%) and Ciracassians (50%),these high percentages leaded us to the degree that this mutation becomes like normal, so we don t call it mutation anymore, it is called single nucleotide polymorphismand considered as normal variation, in Europeans the percentage goes up to 50%, so in a result to this mutation, the reactions that need N5-methyl-tetrahydrofolate will not happen properly. So it is a big problem. Synthesis of amino acids Some of the reactions in degradation share the same process in synthesis of amino acids, only the nonessential amino acids can be synthesized. Essential: Phe, Val, Thr, Trp, Met, Leu, Ile, Lys & His 11 P a g e

12 Nonessential: Ala, Arg, Asp, Asn, Cys, Glu, Gln, Gly, Pro, Ser& Tyr *note that amino acids that start with A,B,C and G are all nonessential, the rest that you have to memorize is proline, serine and tyrosine Nonessential amino acids are synthesized from: 1. Metabolic intermediates, So the final products that produced from the degradation process, can be used in some pathways that produce the amino acids, for example pyruvate can be converted to the amino acids that produced it. 2. Or from the essential amino acids. DONE BY : MOUSA SALAH CORRECTED BY : BAHAA NAJJAR BEST OF LUCK 12 P a g e