WEBVTT 1 00:00:00.080 --> 00:00:03.720 Imagine a three year old child sitting in a clinic's 2 00:00:05.000 --> 00:00:09.160 She's lethargic, her face is severely swollen, and her skin 3 00:00:09.240 --> 00:00:10.279 is actually losing its. 4 00:00:10.160 --> 00:00:12.359 Natural pigment, right, And the craziest part is she's been 5 00:00:12.400 --> 00:00:14.480 consuming calories every day exactly. 6 00:00:14.560 --> 00:00:17.079 I mean, she has enough raw energy to just keep 7 00:00:17.079 --> 00:00:22.079 her heart beating, but on a fundamental cellular level, she 8 00:00:22.239 --> 00:00:23.839 is literally starving to death. 9 00:00:23.960 --> 00:00:26.719 Yeah, her physical blueprint is just completely collapsing. 10 00:00:26.960 --> 00:00:29.920 And today we are going to look at the chemical 11 00:00:29.920 --> 00:00:32.840 code of life to figure out exactly how that is possible, 12 00:00:32.920 --> 00:00:35.960 and more importantly, how we can intervene to save her. 13 00:00:36.119 --> 00:00:39.200 We're looking at what is really the ultimate paradox of 14 00:00:39.240 --> 00:00:40.079 biology here. 15 00:00:40.320 --> 00:00:40.560 Yeah. 16 00:00:40.640 --> 00:00:44.880 You take completely lifeless, non living atoms, arrange them in 17 00:00:44.960 --> 00:00:50.240 these highly specific microscopic structures, and suddenly you, well, you 18 00:00:50.399 --> 00:00:51.880 cross the threshold into life. 19 00:00:51.960 --> 00:00:52.240 Yeah. 20 00:00:52.240 --> 00:00:55.000 And when that arrangement is missing even a single critical piece, 21 00:00:55.039 --> 00:00:57.439 like a specific type of molecule in her child's diet, 22 00:00:57.759 --> 00:01:00.159 the entire dynamic system just starts to break down. 23 00:01:00.079 --> 00:01:03.719 Which is why we're diving straight into the architectural blueprints 24 00:01:03.759 --> 00:01:06.439 of the human body. For today's deep dive. We're acting 25 00:01:06.480 --> 00:01:09.359 as your guides through the chemical language of life. 26 00:01:09.159 --> 00:01:11.840 And we are pulling our insights directly from a massive 27 00:01:11.879 --> 00:01:12.560 source today. 28 00:01:12.799 --> 00:01:16.599 Yeah, the fourth edition of Biochemistry by doctor Yusa Chanarayana 29 00:01:16.680 --> 00:01:20.599 and doctor yu Chakrapani. For anyone studying pharmacy, medicine, or 30 00:01:20.680 --> 00:01:24.000 just trying to seriously understand how the body works, this 31 00:01:24.120 --> 00:01:27.719 text is well, it's essentially the Bible of biochemistry, it 32 00:01:27.799 --> 00:01:30.280 really is. So our mission today is to use it 33 00:01:30.280 --> 00:01:34.640 to bridge that gap between invisible molecular structures and real 34 00:01:34.680 --> 00:01:36.959 world clinical pharmacology. 35 00:01:36.400 --> 00:01:41.200 Because understanding that baseline architecture is completely non negotiable. If 36 00:01:41.239 --> 00:01:44.200 you want to understand drug design in pharmacology, you aren't 37 00:01:44.239 --> 00:01:47.560 just memorizing pathways for an exam, right, You're actually altering 38 00:01:47.599 --> 00:01:50.640 them exactly. You have to know the precise cellular environment 39 00:01:51.040 --> 00:01:54.040 so that when a disease process warps that environment, you 40 00:01:54.120 --> 00:01:56.599 know exactly which molecular lever you need to pull to 41 00:01:56.599 --> 00:01:56.959 fix it. 42 00:01:57.159 --> 00:02:00.519 Okay, let's unpack this by starting with the raw materials 43 00:02:00.519 --> 00:02:02.920 of that environment. So I think of the cells basically 44 00:02:03.200 --> 00:02:05.959 a high tech pharmaceutical manufacturing plant. 45 00:02:06.079 --> 00:02:07.359 That's a great way to look at it. 46 00:02:07.439 --> 00:02:09.599 But the scale of complexity we're dealing with in this 47 00:02:09.639 --> 00:02:13.520 plant is almost hard to visualize. The text points out 48 00:02:13.800 --> 00:02:18.039 that a simple single celled E. Coli bacterium contains about 49 00:02:18.080 --> 00:02:21.039 six thousand different organic compounds. 50 00:02:20.560 --> 00:02:23.080 Which already sounds like a lot, right, But. 51 00:02:23.080 --> 00:02:25.879 A human beings you and I contain around one hundred 52 00:02:25.919 --> 00:02:27.520 thousand different types of molecules. 53 00:02:27.719 --> 00:02:30.199 But you have to think about the underlying simplicity of 54 00:02:30.240 --> 00:02:33.479 that massive number too. What you mean, Well, about ninety 55 00:02:33.479 --> 00:02:36.000 percent of the human bodies dry weight is constructed from 56 00:02:36.080 --> 00:02:41.080 just six elements carbon, hydrogen, oxygen, nitrogen, phosphorus, and sulfur. 57 00:02:41.400 --> 00:02:43.039 Wow, just six. 58 00:02:43.240 --> 00:02:46.120 Yeah, that is the entire raw material catalog for those 59 00:02:46.120 --> 00:02:48.000 one hundred thousand complex compounds. 60 00:02:48.039 --> 00:02:50.240 So like having a Lego set with only six colors, 61 00:02:50.240 --> 00:02:53.400 but somehow you manage to build a fully functioning life 62 00:02:53.439 --> 00:02:56.759 size metropolis. Yes, and out of those six, carbon is 63 00:02:57.240 --> 00:03:01.039 undeniably the MVP I mean. The text calls carbon the 64 00:03:01.159 --> 00:03:03.080 versatile mother of organic molecule. 65 00:03:03.199 --> 00:03:04.199 It really is the mother. 66 00:03:04.680 --> 00:03:08.759 But mechanically speaking, why does carbon get to be the 67 00:03:08.800 --> 00:03:11.479 biological scaffolding for everything? 68 00:03:11.680 --> 00:03:14.800 It all comes down to structural geometry. Carbon has this 69 00:03:14.919 --> 00:03:19.120 incredibly unique ability to form highly stable covalent bonds with 70 00:03:19.159 --> 00:03:22.840 other carbon atoms. It has four valence electrons, meaning it 71 00:03:22.840 --> 00:03:25.280 can actually form four bonds simultaneously. 72 00:03:25.479 --> 00:03:29.120 So it's basically like a four way chemical intersection. It's 73 00:03:29.159 --> 00:03:31.680 able to share electrons in four different directions at once. 74 00:03:31.800 --> 00:03:36.159 Precisely, and because those covalent bonds are so thermodynamically stable, 75 00:03:36.599 --> 00:03:41.080 carbon atoms can link together to create chains of practically unlimited. 76 00:03:40.560 --> 00:03:42.199 Length like long polymers and stuff. 77 00:03:42.280 --> 00:03:46.639 Right, they form giant rings, complex branches, and long twisting backbones. 78 00:03:47.120 --> 00:03:50.719 These carbon structures serve as an unbreakable scaffold, and then 79 00:03:50.879 --> 00:03:53.759 all the other elements like oxygen or nitrogen can just 80 00:03:53.800 --> 00:03:56.280 attach to it to form specific functional groups. 81 00:03:56.319 --> 00:03:56.919 Oh, I see. 82 00:03:56.960 --> 00:04:00.520 Without the sheer physical stability of that carbon carbon intersection, 83 00:04:01.319 --> 00:04:06.319 massive biomolecules like DNA or say, giant therapeutic proteins, they 84 00:04:06.360 --> 00:04:09.080 simply couldn't hold themselves together under the physical stress of 85 00:04:09.120 --> 00:04:09.520 the cell. 86 00:04:09.759 --> 00:04:12.520 Okay, So if carbon is the structural steel, I want 87 00:04:12.520 --> 00:04:14.680 to look at the different rooms inside the cell where 88 00:04:14.680 --> 00:04:17.759 that steel is put to work, the organelles exactly, And 89 00:04:17.800 --> 00:04:21.639 I want to frame these organelles around the idea of vulnerability, because, 90 00:04:21.920 --> 00:04:25.920 as any pharmacy student listening knows, wherever there is a 91 00:04:26.000 --> 00:04:29.920 highly specialized structure. There is the potential for a catastrophic 92 00:04:29.959 --> 00:04:31.680 disease when that structure fails. 93 00:04:31.800 --> 00:04:33.360 That is the basis of pathology. 94 00:04:33.439 --> 00:04:35.319 Yeah, so let's look at the nucleus. It's the heavily 95 00:04:35.319 --> 00:04:39.279 guarded vault holding the DNA. But physically, how do you 96 00:04:39.319 --> 00:04:43.079 cram roughly two meters of DNA into a microscopic space 97 00:04:43.519 --> 00:04:46.199 without it tangling into just an unreadable mess. 98 00:04:46.319 --> 00:04:49.920 The cell solves this mechanical packing problem using specialized basic 99 00:04:49.959 --> 00:04:50.920 proteins called. 100 00:04:50.800 --> 00:04:51.959 Histones his stones. 101 00:04:52.000 --> 00:04:56.160 Okay, yeah, imagine the DNA as a really long, fragile thread. 102 00:04:56.279 --> 00:04:58.480 The cell tightly winds this thread around a core of 103 00:04:58.519 --> 00:05:02.879 histone proteins to forms structural units called nucleosomes. 104 00:05:02.319 --> 00:05:04.279 Like winding thread around a spool. 105 00:05:04.079 --> 00:05:06.879 Exactly like that, and then these nucleosomes coil up even 106 00:05:06.879 --> 00:05:11.160 tighter to form chromosomes. It is an incredibly precise filing system. 107 00:05:11.240 --> 00:05:13.959 But the vulnerability isn't just in the filing. 108 00:05:13.720 --> 00:05:14.439 Where is it. 109 00:05:14.439 --> 00:05:18.040 It's in the walls of the vault itself, the nuclear envelope. 110 00:05:18.079 --> 00:05:20.399 And this is where the text provides a really striking 111 00:05:20.399 --> 00:05:24.480 clinical correlation. It details what happens when the physical structure 112 00:05:24.519 --> 00:05:28.800 that envelope warps, specifically in a disease called Hutchinson Guildford 113 00:05:28.839 --> 00:05:29.800 Progeria syndrome. 114 00:05:30.000 --> 00:05:33.439 Yeah, it is a devastating and very rare condition. It 115 00:05:33.480 --> 00:05:37.319 occurs in roughly one in five million berths. Patients with 116 00:05:37.360 --> 00:05:41.879 progeria experience accelerated aging that basically begins right at birth. 117 00:05:42.079 --> 00:05:45.439 And the root cause isn't like some complex multi organ 118 00:05:45.519 --> 00:05:46.879 failure right now, No, not at all. 119 00:05:46.920 --> 00:05:50.000 It all traces back to a single structural defect at 120 00:05:50.040 --> 00:05:53.759 the subcellular level. It's caused by the accumulation of an 121 00:05:53.839 --> 00:05:56.319 abnormal version of a protein called lamina a. 122 00:05:56.680 --> 00:05:59.079 So lamina a is supposed to be the physical support 123 00:05:59.079 --> 00:06:02.000 beam for the nuclear envelope, but the defective versiin just 124 00:06:02.079 --> 00:06:03.399 warps the wall of the vault. 125 00:06:03.399 --> 00:06:06.279 You've got it completely. It physically distorts the shape of 126 00:06:06.279 --> 00:06:07.279 the nuclear envelope. 127 00:06:07.319 --> 00:06:07.560 Wow. 128 00:06:07.600 --> 00:06:10.639 And because that envelope is tightly regulating everything that goes 129 00:06:10.680 --> 00:06:13.360 in and out of the nucleus, all the signals required 130 00:06:13.399 --> 00:06:18.800 for cellular repair and replication, this structural distortion causes systemic chaos. 131 00:06:19.079 --> 00:06:21.040 The cell just can't regulate itself anymore. 132 00:06:21.120 --> 00:06:24.439 Right, normal cellular function breaks down, which leads directly to 133 00:06:24.480 --> 00:06:27.360 the rapid premature aging we see clinically in these kids. 134 00:06:27.480 --> 00:06:30.439 It's terrifying how a single distorted protein in the wall 135 00:06:30.480 --> 00:06:34.839 of one organelle can cascade into a system wide aging syndrome. 136 00:06:35.319 --> 00:06:38.000 But let's step outside the nucleus and look at the 137 00:06:38.040 --> 00:06:39.120 metabolic engine room. 138 00:06:39.360 --> 00:06:42.759 The mitochondria ah the powerhouse of the cell. 139 00:06:42.879 --> 00:06:47.000 We know it generates atp the energy currency, but structurally 140 00:06:47.160 --> 00:06:51.079 it is incredibly strange. The text emphasizes that it has 141 00:06:51.120 --> 00:06:53.720 a double membrane and the inner one is folded up 142 00:06:53.720 --> 00:06:55.279 into these ridges called christae. 143 00:06:55.399 --> 00:06:57.079 Yeah, to increase surface area, right. 144 00:06:57.360 --> 00:07:00.759 But more importantly, it has its own circular DNA, completely 145 00:07:00.759 --> 00:07:03.560 separate from the nucleus and produces about ten percent of 146 00:07:03.600 --> 00:07:04.480 its own proteins. 147 00:07:04.600 --> 00:07:08.839 The mitochondria is an absolute anatomical anomaly. It operates with 148 00:07:08.959 --> 00:07:12.519 highly independent genetic machinery. It has its own DNA, its 149 00:07:12.560 --> 00:07:16.800 own RNA, and its own unique ribosomes for synthesizing proteins. 150 00:07:16.319 --> 00:07:18.160 Which is so bizarre when you think about it. 151 00:07:18.160 --> 00:07:22.279 It is its structure and function actually closely resemble prokaryotic 152 00:07:22.319 --> 00:07:26.879 cells meaning bacteria. Yeah. This heavily supports the end of 153 00:07:26.920 --> 00:07:31.839 symbiotic theory, the idea that ancient anaerobic cells basically swallowed 154 00:07:31.879 --> 00:07:35.360 aerobic bacteria, and instead of digesting them, they formed a 155 00:07:35.360 --> 00:07:38.399 symbiotic relationship that has lasted a billion years. 156 00:07:38.519 --> 00:07:41.279 Wait, I'm trying to picture the pharmacological implications of this. 157 00:07:42.000 --> 00:07:47.279 If r mitochondria basically evolved from ancient independent bacteria and 158 00:07:47.319 --> 00:07:51.639 they still have their own bacteria like DNA, does that 159 00:07:51.720 --> 00:07:55.720 mean certain drugs might accidentally target our mitochondria because they 160 00:07:55.759 --> 00:07:57.480 mistake them for invading bacteria. 161 00:07:57.680 --> 00:07:59.720 That is a brilliant question. You just hit on one 162 00:07:59.720 --> 00:08:02.879 of the most critical, often overlook dangers in pharmacology. 163 00:08:02.959 --> 00:08:04.199 Oh wow, really, yes. 164 00:08:04.079 --> 00:08:08.480 Absolutely, Because mitochondrial ribosomes are structurally far more similar to 165 00:08:08.560 --> 00:08:10.519 bacterial ribisomes than they are to the rest of the 166 00:08:10.600 --> 00:08:13.439 human cell, certain classes of antibiotics can. 167 00:08:13.319 --> 00:08:15.920 Cross react no way like which ones well. 168 00:08:16.000 --> 00:08:20.519 Drugs like tetracyclines or aminoglycosides they work specifically by inhibiting 169 00:08:20.560 --> 00:08:24.000 bacterial protein synthesis, but at high doses they can slip 170 00:08:24.000 --> 00:08:27.040 into our cells and inhibit our mitochondria protein synthesis too. 171 00:08:27.319 --> 00:08:31.199 Wow. So when you deploy a chemical weapon against a 172 00:08:31.279 --> 00:08:35.720 strep throat infection, you are also exposing the ancestral bacterial 173 00:08:35.759 --> 00:08:39.480 remnants inside your own cells to that exact same weapon. 174 00:08:39.879 --> 00:08:43.440 This is a primary mechanism behind the cellular toxicity of 175 00:08:43.480 --> 00:08:48.200 certain drugs. You cannot properly gauge drug safety without understanding 176 00:08:48.279 --> 00:08:50.759 that evolutionary biochemistry. 177 00:08:50.279 --> 00:08:52.159 That perfectly illustrates the stakes here. 178 00:08:52.320 --> 00:08:54.960 Yeah, okay, let's look at one more sight of vulnerability 179 00:08:55.000 --> 00:08:59.399 before we move on the lysosomes. The cellular recycling centers, Right, 180 00:08:59.440 --> 00:09:03.320 they are essential spherical bags filled with degrading enzymes called hydrolases. 181 00:09:03.720 --> 00:09:06.000 I assume their job is to break down old proteins 182 00:09:06.000 --> 00:09:08.240 and lipids so the raw materials can be reused. 183 00:09:08.320 --> 00:09:11.279 Yeah, they keep the cells inventory in a dynamic, healthy state. 184 00:09:11.600 --> 00:09:15.399 But they aren't perfect incinerators. Some residual products just cannot 185 00:09:15.399 --> 00:09:18.159 be completely broken down by those specific hydrolyses. 186 00:09:18.320 --> 00:09:20.840 Like what the text highlights a substance called lepofusin. 187 00:09:21.039 --> 00:09:24.200 Yes, the wear and tear pigment. So if the lysisome 188 00:09:24.320 --> 00:09:27.919 is full of these powerful degrading enzymes, but it leaves 189 00:09:27.960 --> 00:09:32.440 behind this lipofusin sludge, is that just because our specific 190 00:09:32.600 --> 00:09:36.120 enzymes haven't evolved the chemical keys to unlock that particular 191 00:09:36.240 --> 00:09:37.000 type of waste. 192 00:09:37.039 --> 00:09:42.679 Precisely, lipofusin is a complex, heavily oxidized mixture. It's rich 193 00:09:42.720 --> 00:09:46.080 in lipids and proteins that the lysosomal hydrolases just bounce 194 00:09:46.159 --> 00:09:49.399 right off of. They physically can't cleave the bonds, so 195 00:09:49.399 --> 00:09:51.399 it just sits there. Yeah. So as we age, this 196 00:09:51.480 --> 00:09:55.159 pigment slowly builds up inside our cells, particularly in long 197 00:09:55.159 --> 00:09:58.159 lived cells like neurons and heart muscle cells. It literally 198 00:09:58.200 --> 00:10:01.600 clogs the intracellular space and it is heavily implicating the 199 00:10:01.600 --> 00:10:04.159 fundamental physical process of biological aging. 200 00:10:04.559 --> 00:10:06.639 We will definitely come back to that aging concept at 201 00:10:06.679 --> 00:10:09.879 the end of this deep dive. But those hydrolases inside 202 00:10:09.919 --> 00:10:12.320 the lysis some are actually a perfect pivot point for 203 00:10:12.399 --> 00:10:16.399 us because they are essentially just enzymes acting as biological scissors, right, 204 00:10:16.840 --> 00:10:20.200 And in pharmacology, we don't just study these molecular scissors. 205 00:10:20.200 --> 00:10:22.240 We actually weaponize them as therapies. 206 00:10:22.519 --> 00:10:27.440 We do. Enzymes are the incredibly precise biological catalysts driving 207 00:10:27.559 --> 00:10:30.879 every reaction in the body. Nearly all of them are proteins. 208 00:10:31.519 --> 00:10:34.440 But to understand how we use them therapeutically, we have 209 00:10:34.480 --> 00:10:35.919 to look at their anatomy first. 210 00:10:36.080 --> 00:10:37.200 Okay, break it down for us. 211 00:10:37.679 --> 00:10:40.960 The fully active functional unit of an enzyme is called 212 00:10:40.960 --> 00:10:43.799 a hollow enzyme. But a hollow enzyme is actually a 213 00:10:43.799 --> 00:10:46.960 two part machine. First, you have the apoenzyme, which is 214 00:10:47.000 --> 00:10:48.320 the bulky protein portion. 215 00:10:48.519 --> 00:10:51.279 But the a poenzyme alone is often completely inactive. 216 00:10:51.360 --> 00:10:51.440 Right. 217 00:10:51.519 --> 00:10:53.399 It's like a car without an ignition. 218 00:10:53.120 --> 00:10:55.799 Key, exactly like that. It needs a helper molecule to 219 00:10:55.840 --> 00:10:58.519 activate it. That helper is the coenzyme, which is a 220 00:10:58.639 --> 00:11:00.360 non protein organic. 221 00:11:00.120 --> 00:11:01.519 Molecule, and they lock together. 222 00:11:01.720 --> 00:11:05.799 Yeah, the coenzyme plus the coenzyme locked together to form 223 00:11:05.840 --> 00:11:07.000 the active holoenzyme. 224 00:11:07.200 --> 00:11:10.120 And the text points out something fascinating about those coenzymes. 225 00:11:10.480 --> 00:11:12.919 They don't just appear out of nowhere. They are very 226 00:11:12.960 --> 00:11:16.519 often derived directly from water soluble B complex vitamins. 227 00:11:16.759 --> 00:11:20.799 This is the bridge between nutrition and biochemistry. The physiological 228 00:11:20.799 --> 00:11:24.440 functions of B complex vitamins are literally exerted through their 229 00:11:24.559 --> 00:11:25.639 role as coenzymes. 230 00:11:25.759 --> 00:11:26.840 That makes so much sense. 231 00:11:26.919 --> 00:11:30.200 So when a patient presents with a severe vitamin B defficiency, 232 00:11:30.559 --> 00:11:34.080 they aren't just feeling tired for some abstract reason. They 233 00:11:34.120 --> 00:11:38.399 are physically missing the vital non protein components required to 234 00:11:38.399 --> 00:11:40.159 turn on their enzymatic machinery. 235 00:11:40.399 --> 00:11:44.480 Wow. Without the coenzyme, the halo enzyme just can't form. 236 00:11:44.320 --> 00:11:47.879 Right, and the specific metabolic reactions required for energy production 237 00:11:48.159 --> 00:11:49.679 just grind to a halt. 238 00:11:49.879 --> 00:11:52.840 So understanding the two part structure is crucial. Yeah, but 239 00:11:52.919 --> 00:11:55.320 let's look at how we take fully functioning enzymes and 240 00:11:55.440 --> 00:11:59.840 use them as drugs. The text lists streptokines in eurokinase. 241 00:12:00.480 --> 00:12:03.679 I see they're used for blood clots. But mechanically, how 242 00:12:03.720 --> 00:12:07.799 does injecting a protein actually dissolve a solid physical blockage 243 00:12:07.799 --> 00:12:08.679 in a patient's vein. 244 00:12:08.879 --> 00:12:12.919 Well. Structokinase and eurokinase are known as thrombolytics. When a 245 00:12:12.960 --> 00:12:15.960 patient comes into the emergency room with a myocardial infarction 246 00:12:16.159 --> 00:12:19.039 a heart attack caused by a blood clot, you administer 247 00:12:19.159 --> 00:12:22.639 these enzymes intravenously. The clot is held together by a tough, 248 00:12:22.679 --> 00:12:26.360 fibrous protein called fibrin. These enzymes circulate in the blood, 249 00:12:26.519 --> 00:12:29.600 find the clot, and literally act as molecular scissors. They 250 00:12:29.759 --> 00:12:32.240 rapidly catalyze the breakdown of that fibrin mesh. 251 00:12:32.320 --> 00:12:33.279 'll you just chop it up? 252 00:12:33.480 --> 00:12:36.799 They cut the physical structure of the clot apart, restoring 253 00:12:36.879 --> 00:12:38.279 blood flow to the heart muscle. 254 00:12:38.440 --> 00:12:42.240 That is a very direct mechanical intervention. A But here's 255 00:12:42.279 --> 00:12:45.799 where it gets really interesting. The next therapeutic example from 256 00:12:45.799 --> 00:12:47.440 the text is asparogenase. 257 00:12:47.720 --> 00:12:47.919 Ah. 258 00:12:48.080 --> 00:12:52.080 Yes, it's used in cancer therapy, specifically for certain types 259 00:12:52.159 --> 00:12:55.000 of leukemia. I was reading this section and it is 260 00:12:55.080 --> 00:12:59.720 essentially targeted biochemical warfare. You are starving a cancer cell 261 00:12:59.759 --> 00:13:01.720 today without touching the healthy cells. 262 00:13:01.759 --> 00:13:04.159 What's fascinating here is that it's one of the most 263 00:13:04.240 --> 00:13:08.879 brilliant exploitations of a metabolic vulnerability we have in oncology. 264 00:13:09.440 --> 00:13:11.879 We have to look at the amino acid of sparagen. Okay, 265 00:13:12.120 --> 00:13:16.320 spirit Most normal, healthy cells in the human body possess 266 00:13:16.399 --> 00:13:20.679 the internal enzymatic machinery required to synthesize their own asparagen. 267 00:13:21.039 --> 00:13:23.320 They don't need to hunt for it in the bloodstream. 268 00:13:22.879 --> 00:13:24.639 They just make it in house exactly. 269 00:13:24.759 --> 00:13:28.600 However, certain leukemic tumor cells have a genetic defect. They 270 00:13:28.600 --> 00:13:31.440 have lost the ability to make their own asparagen. 271 00:13:31.039 --> 00:13:34.120 So they are entirely dependent on scavenging it from the 272 00:13:34.159 --> 00:13:37.960 host blood plasma just to multiply and survive. Why doesn't 273 00:13:37.960 --> 00:13:40.279 this starve the patient's normal cells too, though. 274 00:13:40.240 --> 00:13:42.960 Because, like we said, the normal cells can just quietly 275 00:13:43.000 --> 00:13:46.639 synthesize their own supply internally, so they are completely fine. 276 00:13:47.159 --> 00:13:50.159 But the tumor cells, which rely one hundred percent on 277 00:13:50.200 --> 00:13:53.080 the plasma supply are suddenly cut off. 278 00:13:53.200 --> 00:13:57.080 Oh, I see, because the drug asparagenase destroys the plasma supply. 279 00:13:57.360 --> 00:14:01.440 Yes, when you administer asparagenase, it circulates in the patient's 280 00:14:01.480 --> 00:14:04.679 plasma and actively destroys all the circulating asparaiture. 281 00:14:04.720 --> 00:14:08.679 That is incredible. They're starved of this essential building block, 282 00:14:08.840 --> 00:14:12.320 which drastically depresses their viability and halts their multiplication. 283 00:14:12.600 --> 00:14:15.360 You aren't poisoning the cell directly with a toxic chemical. 284 00:14:15.399 --> 00:14:18.279 You are just removing the one specific nutrient it uniquely 285 00:14:18.320 --> 00:14:22.200 needs to survive. It is a perfect pharmacological target. 286 00:14:22.480 --> 00:14:25.440 That is the beauty of biochemistry right there. And these 287 00:14:25.519 --> 00:14:28.240 enzymes aren't just used as drugs, they are also highly 288 00:14:28.240 --> 00:14:32.480 precise analytical tools. The text discusses using glucose, oxidase and 289 00:14:32.519 --> 00:14:36.200 peroxidase as diagnostic reagents right in the lab. Yeah, in 290 00:14:36.240 --> 00:14:39.039 a clinical lab. When you take a messy blood sample 291 00:14:39.080 --> 00:14:42.000 full of thousands of different compounds, how do you measure 292 00:14:42.159 --> 00:14:44.159 just the glucose with absolute certainty. 293 00:14:44.399 --> 00:14:48.080 Well, older chemical methods can sometimes be nonspecific, you know, 294 00:14:48.279 --> 00:14:52.200 accidentally reacting with multiple different sugars or reducing agents in 295 00:14:52.240 --> 00:14:54.879 the blood, which gives you a falsely high reading. 296 00:14:54.679 --> 00:14:56.320 Which is bad if you're trying to dose s insulin. 297 00:14:56.480 --> 00:15:00.759 Very bad. But enzymes have strict substrate special efficity. They 298 00:15:00.759 --> 00:15:04.879 only fit one lock. By using glucose oxidase, the laboratory 299 00:15:04.919 --> 00:15:10.120 test reacts exclusively with glucose, completely ignoring every other molecule 300 00:15:10.120 --> 00:15:10.399 in the. 301 00:15:10.360 --> 00:15:11.919 Plasma, so it's perfectly accurate. 302 00:15:12.120 --> 00:15:16.799 It provides highly accurate plasma glucose estimations, which is the 303 00:15:17.159 --> 00:15:21.159 absolute bedrock of diagnosing and managing conditions like diabetes. 304 00:15:21.320 --> 00:15:24.240 So enzymes build the architecture of the cell. They are 305 00:15:24.279 --> 00:15:27.279 weaponized as drugs, and they are used to diagnose disease. 306 00:15:27.840 --> 00:15:30.840 But to keep all these intricate molecular machines running, the 307 00:15:30.879 --> 00:15:34.399 cell needs currency. It needs fuel always, which brings up 308 00:15:34.399 --> 00:15:37.399 the field of bio energetics. How does scientists actually map 309 00:15:37.440 --> 00:15:40.600 out these invisible currency exchanges to figure out where to 310 00:15:40.600 --> 00:15:41.960 intervene with new drugs. 311 00:15:42.159 --> 00:15:46.440 Bio Energetics or biochemical thermodynamics, is the study of energy 312 00:15:46.519 --> 00:15:50.399 changes in these reactions. The cell's whole goal is to 313 00:15:50.440 --> 00:15:55.159 couple exorgonic reactions, which release energy, with endergonic reactions, which 314 00:15:55.240 --> 00:15:56.320 consume energy. 315 00:15:56.440 --> 00:15:59.120 Okay, so it uses the breakdown of molecules to fuel 316 00:15:59.200 --> 00:16:01.919 the building of others exactly. And the text is very 317 00:16:01.919 --> 00:16:04.480 specific about the term free energy. We aren't just talking 318 00:16:04.480 --> 00:16:06.799 about heat radiating off a reaction right now. 319 00:16:06.840 --> 00:16:10.720 No, free energy is this specific, quantifiable amount of energy 320 00:16:10.799 --> 00:16:14.960 actually available to do biological work. And the universal currency 321 00:16:15.000 --> 00:16:20.759 that captures and carries this free energy is ATP adnisine triphosphate. 322 00:16:20.159 --> 00:16:21.120 The famous ATP. 323 00:16:21.440 --> 00:16:24.519 Right when your cell breaks down glucose, it captures that 324 00:16:24.639 --> 00:16:27.279 released free energy and stores it in the high energy 325 00:16:27.279 --> 00:16:30.200 phosphate bonds of ATP, ready to be spent wherever the 326 00:16:30.240 --> 00:16:30.960 cell needs it. 327 00:16:31.080 --> 00:16:33.840 But the metabolic map of how glucose actually gets turned 328 00:16:33.879 --> 00:16:36.679 into ATP looks like a subway map of Tokyo one 329 00:16:36.759 --> 00:16:40.080 hundred times more tangled. If you're a biochemist in a lab, 330 00:16:40.200 --> 00:16:42.960 how do you actually figure out the sequence of these reactions? 331 00:16:43.080 --> 00:16:43.919 You use tools. 332 00:16:44.039 --> 00:16:46.639 The text introduces this tool called metabolic probes. 333 00:16:46.960 --> 00:16:51.879 Yes, metabolic probes are brilliant tools used to create highly 334 00:16:51.919 --> 00:16:55.919 specific traffic jams in these pathways. The two most common 335 00:16:55.919 --> 00:16:59.399 types are chemical metabolic inhibitors and genetic mutations. 336 00:16:59.799 --> 00:17:01.840 Does as a traffic jam help you map it out? 337 00:17:01.919 --> 00:17:05.559 The logic is straightforward. If you drop a specific inhibitor 338 00:17:05.599 --> 00:17:09.039 into a cell to block one specific enzyme in a pathway, 339 00:17:09.359 --> 00:17:13.680 the intermediate compound right before that blockade will massively build up, 340 00:17:13.839 --> 00:17:16.599 and all the products after the blockade will just disappear. 341 00:17:16.759 --> 00:17:18.680 Oh, I get it. It's like trying to map a 342 00:17:18.720 --> 00:17:22.440 highway system in the dark. If you artificially close a bridge, 343 00:17:22.799 --> 00:17:25.519 you can figure out exactly where the closure is by 344 00:17:25.559 --> 00:17:27.799 flying a helicopter over and seeing where all the headlights 345 00:17:27.839 --> 00:17:28.359 are backed up. 346 00:17:28.400 --> 00:17:30.960 That is the perfect analogy. Yes, the text gives a 347 00:17:30.960 --> 00:17:35.279 classic historical example of this, elucidating the electron transport chain. 348 00:17:35.759 --> 00:17:39.119 The electron transport chain is a series of protein complexes 349 00:17:39.119 --> 00:17:42.440 in the inner mitochondrial membrane that pass electrons down a 350 00:17:42.480 --> 00:17:45.960 line to generate massive amounts of ATP. For a long time, 351 00:17:46.039 --> 00:17:49.880 scientists knew the carriers existed, but they didn't know the sequential. 352 00:17:49.480 --> 00:17:51.559 Order, so they closed the bridges by. 353 00:17:51.480 --> 00:17:56.640 Using specific metabolic inhibitors, essentially cellular poisons that target specific complexes. 354 00:17:57.160 --> 00:18:00.480 They could observe which carriers remain loaded with electrics in 355 00:18:00.519 --> 00:18:02.160 which ones were suddenly emptied. 356 00:18:02.599 --> 00:18:07.039 By systematically closing different bridges with different poisons, they mapped 357 00:18:07.079 --> 00:18:11.319 the exact sequential order of the entire chain. And for 358 00:18:11.359 --> 00:18:15.000 a pharmacy student listening, why is mastering the concept of 359 00:18:15.039 --> 00:18:17.440 a metabolic probe so foundational? 360 00:18:17.799 --> 00:18:20.279 If we connect this to the bigger picture, rational drug 361 00:18:20.319 --> 00:18:24.519 design is essentially the process of creating highly targeted metabolic probes. 362 00:18:24.559 --> 00:18:27.559 Oh interesting, Many of the most effective therapeutics we prescribe 363 00:18:27.640 --> 00:18:31.599 are just specific metabolic inhibitors. If a patient suffers from 364 00:18:31.640 --> 00:18:35.039 a metabolic disease where their body produces a toxic excess 365 00:18:35.039 --> 00:18:38.279 of a certain compound, a pharmacologist needs to know exactly 366 00:18:38.279 --> 00:18:41.240 which enzyme in that invisible highway they can safely inhibit 367 00:18:41.319 --> 00:18:41.880 to stop the. 368 00:18:41.839 --> 00:18:44.720 Production without shutting down a vital detour somewhere else. 369 00:18:44.880 --> 00:18:47.960 Exactly, You cannot design a safe roadblock if you don't 370 00:18:47.960 --> 00:18:50.920 possess a flawlessly accurate map of the highway. 371 00:18:50.720 --> 00:18:53.640 That brings us full circle to the very real stakes 372 00:18:53.640 --> 00:18:57.039 of that highway system. Because ultimately, the raw materials and 373 00:18:57.079 --> 00:19:00.519 the energy for these pathways don't just magically materi cerialize 374 00:19:00.559 --> 00:19:03.519 inside the cell. They are imported from the outside world 375 00:19:03.559 --> 00:19:07.200 through our diet, right and when that macrosupply chain fails, 376 00:19:07.359 --> 00:19:10.039 the microscopic machinery we've been talking about grinds to a 377 00:19:10.079 --> 00:19:12.400 halt leading directly to clinical disease. 378 00:19:12.799 --> 00:19:17.720 The complex macromolecules we consume, so carbohydrates, proteins, lipids, they 379 00:19:17.799 --> 00:19:21.880 must first be broken down by digestive enzymes, specifically hydrolases 380 00:19:22.240 --> 00:19:23.920 in the gastrointestinal tract. 381 00:19:24.079 --> 00:19:25.559 They get chopped up, they have to. 382 00:19:25.480 --> 00:19:31.000 Be dismantled into their monomeric building blocks marisacharides, individual amino acids, 383 00:19:31.039 --> 00:19:34.480 and fatty acids. Only then can they be absorbed by 384 00:19:34.480 --> 00:19:37.640 the intestinal mucosal cells and delivered via the bloodstream to 385 00:19:37.640 --> 00:19:39.160 fuel the cellular factory. 386 00:19:39.240 --> 00:19:41.640 Which brings us back to the image we started with today, 387 00:19:42.000 --> 00:19:44.640 the three year old child in the clinic. The text 388 00:19:44.680 --> 00:19:47.559 provides a sobering case study in the appendix that perfectly 389 00:19:47.559 --> 00:19:51.119 bridges the gap between macronutrition and microbiochemistry. 390 00:19:51.200 --> 00:19:52.359 It's a very important case. 391 00:19:52.599 --> 00:19:57.119 This young girl presents with stunted growth, extreme apathy, discoloration 392 00:19:57.200 --> 00:20:00.680 of her skin and hair, and severe edema, massive fluid 393 00:20:00.720 --> 00:20:05.119 and attention, particularly in her legs, hands, and this swollen moonface. 394 00:20:05.279 --> 00:20:09.079 These are textbook clinical signs and the diagnosis hinges entirely 395 00:20:09.119 --> 00:20:12.160 on her dietary history. The text notes she was breastfed 396 00:20:12.240 --> 00:20:14.400 until she was two, but for the past year her 397 00:20:14.440 --> 00:20:18.039 diet consisted almost exclusively of dilute buffalo milk and a 398 00:20:18.039 --> 00:20:19.920 small quantity of rice with ghee. 399 00:20:20.359 --> 00:20:22.680 When we look at that diet through the biochemical lens 400 00:20:22.680 --> 00:20:25.519 we've built today, what is fundamentally missing. 401 00:20:26.400 --> 00:20:29.519