PROGRAM KBKPROGRAM KBKFK-UKIFK-UKI

PROTEIN BIOSYNTHESIS

Prof. Dr. drh. Maria Bintang, MSGURU BESAR BIOKIMIA

REFERENCESREFERENCES

Lehninger. 2000. Lehninger. 2000. Principles of biochemistryPrinciples of biochemistry 3rd Ed. 3rd Ed. Michael W. KingMichael W. King. 2006. . 2006. Medical BiochemistryMedical Biochemistry.. Murray R K, Granner D k, Mayers P a & Rodwell V w. Murray R K, Granner D k, Mayers P a & Rodwell V w.

2003. Harper’s Illustrated Biochemistry. 2003. Harper’s Illustrated Biochemistry. 2626th th Ed.Ed. Pratt,C.W.and Cornely K. 2004. Pratt,C.W.and Cornely K. 2004. Essential Essential

BiochemistryBiochemistry. Wiley International Edition.. Wiley International Edition. Stryer, Lubert 1995. Biochemistry.4th Stryer, Lubert 1995. Biochemistry.4th Ed.

Aminoacyl tRNASintetase + ATP

Translation : ELONGASI

Translation : ELONGASIPeptidyl transferase + EF1 + GTP

EF2

RF + GTP

BASE ANALOGS ALKYLATING AGENT

HYDROXILATING AGENT DEAMINATING AGENT

INTERCALATNG AGENT

Inhibitor of Protein Synthesis in EukaryotesInhibitor of Protein Synthesis in Eukaryotes

Abrin, Ricin Abrin, Ricin →→ Inhibits binding of aminoacyl t-RNAInhibits binding of aminoacyl t-RNA Diphtheria toxinDiphtheria toxin →→ Catalyzes a reaction between NAD and EFCatalyzes a reaction between NAD and EF2 2 to to yield an yield an

inactive factor. Inhibits translocationinactive factor. Inhibits translocation Chloramphenicol*Chloramphenicol* →→ Inhibits peptidyltransferase of mitochondrial Inhibits peptidyltransferase of mitochondrial

ribosomes. Is inactive against cytoplasmic ribosomesribosomes. Is inactive against cytoplasmic ribosomes Puromycin*Puromycin* →→ Causes premature chain termination by acting Causes premature chain termination by acting as an as an

analogue of charged t-RNAanalogue of charged t-RNA Fusidic acid*Fusidic acid* →→ Inhibits translocation by altering an elongation Inhibits translocation by altering an elongation factorfactor CycloheximideCycloheximide →→ Inhibits peptidyltransferaseInhibits peptidyltransferase PactamycinPactamycin →→ Inhibits positioning of t-RNAInhibits positioning of t-RNA11

MetMet on the 40S ribosome on the 40S ribosome ShowdomycinShowdomycin →→ Inhibits formation of the EFInhibits formation of the EF22-tRNA-tRNA11

MetMet GTP GTP ccomplexomplex SparsomycinSparsomycin →→ Inhibits translocationInhibits translocation

*also active on prokaryotic ribosomes

Antibiotics Inhibitor of Protein Synthesis in Antibiotics Inhibitor of Protein Synthesis in ProkaryotesProkaryotes

TetracyclineTetracycline Inhibits positioning of Inhibits positioning of t-t-TTNA on A side in ribosomeNA on A side in ribosome

StrStreeptomycinptomycin Inhibits formation of the EFInhibits formation of the EF22 --tRNAtRNA11

MetMet on the 30 S ribosome on the 30 S ribosome

ChloramphenicolChloramphenicol Inhibits Inhibits peptidyltransferase peptidyltransferase on ribosomeon ribosome

ErythromycinErythromycin Inhibits translocationInhibits translocation

RifamycinRifamycin Inhibits RNA synthesis Inhibits RNA synthesis binding to RNA polymerasebinding to RNA polymerase

Biosinthesis Protein disordersBiosinthesis Protein disorders Lactose Intolerance

Lactose intolerance is a clinical syndrome of 1 or more of the following: abdominal pain, diarrhea, nausea, flatulence, and/or bloating after the ingestion of lactose or lactose-containing food substancesPrimary : Lactase Deficiency (genetic)Secondary : lactose malabsorption

ThalassemiaThalassemia Thalassemia is a heterogenous group of haemopoetic disorder which results Thalassemia is a heterogenous group of haemopoetic disorder which results

from genetic defect in either one or both polypeptide chains of the from genetic defect in either one or both polypeptide chains of the haemoglobin moleculeshaemoglobin molecules. . Reduced synthesis of one of the globin chains causes the formation of abnormal hemoglobin molecules, and this in turn causes the anemia which is the characteristic presenting symptom of the thalassemias.

Normal hemoglobin, also called hemoglobin A, has four protein chains—two Normal hemoglobin, also called hemoglobin A, has four protein chains—two alpha globin and two beta globin. The two major types of, alpha and beta, are alpha globin and two beta globin. The two major types of, alpha and beta, are named after defects in these protein chains named after defects in these protein chains

αα – – thalassemia : thalassemia : Four genes are needed to make enough alpha globin protein chains. Alpha Four genes are needed to make enough alpha globin protein chains. Alpha

thalassemia trait occurs when one or two of the four genes are missing. If more thalassemia trait occurs when one or two of the four genes are missing. If more than two genes are missing, the result is moderate to severe anemia.than two genes are missing, the result is moderate to severe anemia.

The most severe form of alpha thalassemia is known as alpha thalassemia major or The most severe form of alpha thalassemia is known as alpha thalassemia major or hydrops fetalis. Babies with this disorder usually die before or shortly after birth. hydrops fetalis. Babies with this disorder usually die before or shortly after birth.

ββ – – thalassemia : thalassemia : Two genes (one from each parent) are needed to make enough beta globin protein Two genes (one from each parent) are needed to make enough beta globin protein

chains. Beta thalassemia occurs when one or both genes are altered. chains. Beta thalassemia occurs when one or both genes are altered. The severity of beta thalassemia depends on how badly one or both genes are The severity of beta thalassemia depends on how badly one or both genes are

affected. If both genes are affected, the result is moderate to severe anemia. The affected. If both genes are affected, the result is moderate to severe anemia. The severe form of beta thalassemia also is known as thalassemia major or Cooley's severe form of beta thalassemia also is known as thalassemia major or Cooley's anemia. anemia.

Symptom of thalassemia Symptom of thalassemia : : FatiqueFatique WeaknessWeakness Pale appearance Pale appearance Joundice Joundice Protruding abdomen Protruding abdomen Spleen enlargement Spleen enlargement Liver enlargement Liver enlargement Shortness of breath Shortness of breath Heart enlargement Heart enlargement Dark urine Dark urine

HypoalbuminemiaHypoalbuminemia Hypoalbuminemia is a deficit of albumin in the blood, Hypoalbuminemia is a deficit of albumin in the blood,

which which produced by liver produced by liver The causes of hypoalbuminemia are : The causes of hypoalbuminemia are :

Renal (kidney) dysfunction Renal (kidney) dysfunction Liver disease Liver disease Inflammatory bowel disease Inflammatory bowel disease Infections, such as tuberculosis Infections, such as tuberculosis

SymptomSymptom Blood albumin levels are significantly loweredBlood albumin levels are significantly lowered Muscle weakness, fatigue, or cramps, poor appetite, Muscle weakness, fatigue, or cramps, poor appetite,

swelling in one part of your body (such as your legs), swelling in one part of your body (such as your legs), abdomen is swollen with fluid (called, ascites)abdomen is swollen with fluid (called, ascites)

Albumin levels below 3.5 g/dl Albumin levels below 3.5 g/dl

Liver fibrosis The Fibrosis Process

The injury or death (necrosis) of hepatocytes stimulates inflammatory immune cells to release cytokines, growth factors, and other chemicals. These chemical messengers direct support cells in the liver called hepatic stellate cells to activate and produce collagen, glycoproteins (such as fibronectin), proteoglycans, and other substances. These substances are deposited in the liver, causing the buildup of extracellular matrix (nonfunctional connective tissue). At the same time, the process of breaking down or degrading collagen is impaired. In a healthy liver, the synthesis (fibrogenesis) and breakdown (fibrolysis) of matrix tissue are in balance. Fibrosis occurs when excessive scar tissue builds up faster than it can be broken down.

Symptom of liver fibrosis Nausea, poor appetite, accumulation of fluid in the abdomen Nausea, poor appetite, accumulation of fluid in the abdomen

(ascites)(ascites) SGOT and SGPT increase USG → Liver enlargement

Liver cirrhosis Cirrhosis of the liver refers to scarring of the liver which results in

abnormal liver function as a consequence of chronic (long-term) liver injury.

Ongoing injury leads to the development of scar tissue in the liver, a process called fibrosis, because of collagen synthesis disorder.

Disorders of albumin synthesis (liver cirrhosis, malabsorption, nephrosis and protein-losing enteropathy)

SGOT and SGPT increase – USG : LIVER SHRINK Symptom of liver cirrhosis : Symptom of liver cirrhosis :

Symptoms at first : The two major problems that eventually cause symptoms Symptoms at first : The two major problems that eventually cause symptoms are loss of functioning liver cells and distortion of the liver caused by scarring. are loss of functioning liver cells and distortion of the liver caused by scarring. The person may experience The person may experience fatigue, weakness, and exhaustion. Loss of fatigue, weakness, and exhaustion. Loss of appetite is usual, often with nausea and weight loss. appetite is usual, often with nausea and weight loss. Later stages Later stages : jaundice : jaundice may occur caused by the buildup of bile pigment that is may occur caused by the buildup of bile pigment that is passed by the liver into the intestine. Some people with cirrhosis experience passed by the liver into the intestine. Some people with cirrhosis experience itching due to bile products that are deposited in the skin. Gallstones often itching due to bile products that are deposited in the skin. Gallstones often form because not enough bile reaches the gallbladder. may develop fluid form because not enough bile reaches the gallbladder. may develop fluid retention in the abdomen which may be complicated by infections. retention in the abdomen which may be complicated by infections.

Muscle atrophyMuscle atrophy Muscle atrophy occurs by a change in the normal balance Muscle atrophy occurs by a change in the normal balance

between protein synthesis and protein degradation. between protein synthesis and protein degradation. The simple loss of muscle mass (The simple loss of muscle mass (atrophy), or the age-related ), or the age-related

decrease in muscle function (decrease in muscle function (sarcopenia). ). There are other diseases which may be caused by structural There are other diseases which may be caused by structural

defects in the muscle (defects in the muscle (muscular dystrophy), ), Or by inflammatory reactions in the body directed against Or by inflammatory reactions in the body directed against

muscle (the myopathies). muscle (the myopathies). Myoglobin can serve as a biomarker of heart attack, since blood

myoglobin levels rise in two to three hours following muscle injury.

Myoglobin is released from damaged muscle tissue