from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.units import cm, mm
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.platypus.flowables import Flowable
from reportlab.graphics.shapes import (
    Drawing, Rect, Circle, Ellipse, String, Arrow,
    Line, Polygon, Group
)
from reportlab.graphics import renderPDF
from reportlab.graphics.shapes import Drawing, Rect, Ellipse, String, Line, Polygon, Circle
import math

# ── Color Palette ──────────────────────────────────────────────────────────────
DEEP_NAVY    = colors.HexColor("#0D1B2A")
ROYAL_BLUE   = colors.HexColor("#1B4F8A")
TEAL         = colors.HexColor("#0F7B8C")
ACCENT_GOLD  = colors.HexColor("#E8A020")
ACCENT_GREEN = colors.HexColor("#2EAA6E")
ACCENT_RED   = colors.HexColor("#C0392B")
ACCENT_PURP  = colors.HexColor("#7B2D8B")
LIGHT_BLUE   = colors.HexColor("#D6EAF8")
LIGHT_GREEN  = colors.HexColor("#D5F5E3")
LIGHT_GOLD   = colors.HexColor("#FEF9E7")
LIGHT_PURP   = colors.HexColor("#F5EEF8")
LIGHT_RED    = colors.HexColor("#FDEDEC")
WHITE        = colors.white
DARK_GRAY    = colors.HexColor("#2C3E50")
MID_GRAY     = colors.HexColor("#7F8C8D")
LIGHT_GRAY   = colors.HexColor("#ECF0F1")
MITO_COLOR   = colors.HexColor("#FFF3CD")
CYTO_COLOR   = colors.HexColor("#D1ECF1")
MITO_BORDER  = colors.HexColor("#E6A817")
CYTO_BORDER  = colors.HexColor("#17A2B8")

W, H = A4  # 595 x 842 pts

# ── Styles ─────────────────────────────────────────────────────────────────────
styles = getSampleStyleSheet()

def make_style(name, parent='Normal', **kw):
    return ParagraphStyle(name, parent=styles[parent], **kw)

cover_title = make_style('CoverTitle', fontSize=32, textColor=WHITE,
                          leading=38, alignment=TA_CENTER, fontName='Helvetica-Bold')
cover_sub   = make_style('CoverSub',   fontSize=16, textColor=LIGHT_BLUE,
                          leading=22, alignment=TA_CENTER)
cover_auth  = make_style('CoverAuth',  fontSize=11, textColor=ACCENT_GOLD,
                          alignment=TA_CENTER)

section_h   = make_style('SectionH', fontSize=15, textColor=WHITE,
                          leading=20, fontName='Helvetica-Bold', alignment=TA_CENTER)
h2          = make_style('H2', fontSize=13, textColor=ROYAL_BLUE,
                          leading=18, fontName='Helvetica-Bold', spaceAfter=4)
h3          = make_style('H3', fontSize=11, textColor=TEAL,
                          leading=15, fontName='Helvetica-Bold', spaceAfter=3)
body        = make_style('Body', fontSize=9.5, textColor=DARK_GRAY,
                          leading=14, spaceAfter=3, alignment=TA_JUSTIFY)
bullet_s    = make_style('Bullet', fontSize=9.5, textColor=DARK_GRAY,
                          leading=13, leftIndent=14, firstLineIndent=-10, spaceAfter=2)
small       = make_style('Small', fontSize=8.5, textColor=MID_GRAY, leading=12)
caption     = make_style('Caption', fontSize=8, textColor=MID_GRAY,
                          alignment=TA_CENTER, fontName='Helvetica-Oblique')
highlight   = make_style('Highlight', fontSize=9.5, textColor=DARK_GRAY,
                          leading=13, backColor=LIGHT_GOLD, leftIndent=8,
                          rightIndent=8, borderPadding=4)
alert       = make_style('Alert', fontSize=9.5, textColor=ACCENT_RED,
                          leading=13, fontName='Helvetica-Bold')

def b(t): return f"<b>{t}</b>"
def col(t, c): return f'<font color="{c}">{t}</font>'
def bullet(t): return Paragraph(f"• {t}", bullet_s)
def hline(): return HRFlowable(width="100%", thickness=0.5, color=LIGHT_GRAY,
                                spaceAfter=4, spaceBefore=4)

# ── Section Banner ─────────────────────────────────────────────────────────────
class SectionBanner(Flowable):
    def __init__(self, text, bg=ROYAL_BLUE, w=None, h=26):
        super().__init__()
        self.text = text
        self.bg = bg
        self._w = w or (W - 3*cm)
        self._h = h
    def wrap(self, aw, ah): return self._w, self._h + 6
    def draw(self):
        c = self.canv
        c.setFillColor(self.bg)
        c.roundRect(0, 0, self._w, self._h, 5, fill=1, stroke=0)
        c.setFillColor(WHITE)
        c.setFont('Helvetica-Bold', 12)
        c.drawCentredString(self._w/2, 7, self.text)

# ── Key Box ────────────────────────────────────────────────────────────────────
class KeyBox(Flowable):
    def __init__(self, lines, bg=LIGHT_GOLD, border=ACCENT_GOLD, w=None):
        super().__init__()
        self.lines = lines
        self.bg = bg
        self.border = border
        self._w = w or (W - 3*cm)
    def wrap(self, aw, ah):
        self._h = len(self.lines) * 16 + 16
        return self._w, self._h
    def draw(self):
        c = self.canv
        c.setFillColor(self.bg)
        c.setStrokeColor(self.border)
        c.setLineWidth(1.5)
        c.roundRect(0, 0, self._w, self._h, 6, fill=1, stroke=1)
        c.setFillColor(DARK_GRAY)
        for i, line in enumerate(self.lines):
            y = self._h - 14 - i*16
            if line.startswith('★'):
                c.setFont('Helvetica-Bold', 9)
                c.setFillColor(ACCENT_RED)
            else:
                c.setFont('Helvetica', 9)
                c.setFillColor(DARK_GRAY)
            c.drawString(10, y, line)

# ══════════════════════════════════════════════════════════════════════════════
#  DIAGRAM 1 – Full Urea Cycle
# ══════════════════════════════════════════════════════════════════════════════
def draw_urea_cycle(dw=500, dh=460):
    d = Drawing(dw, dh)
    cx, cy = dw/2, dh/2 - 10

    # ── Background compartments ───────────────────────────────────────────────
    # Mitochondria oval
    mito_rx, mito_ry = 195, 185
    d.add(Ellipse(cx, cy+18, mito_rx, mito_ry,
                  fillColor=MITO_COLOR, strokeColor=MITO_BORDER,
                  strokeWidth=2.5, strokeDashArray=[5,3]))
    d.add(String(cx-40, cy+mito_ry-12, "MITOCHONDRIA",
                 fontName='Helvetica-Bold', fontSize=8,
                 fillColor=MITO_BORDER))

    # Cytoplasm rectangle outside
    d.add(Rect(2, 2, dw-4, dh-4,
               fillColor=CYTO_COLOR, strokeColor=CYTO_BORDER,
               strokeWidth=1.5, strokeDashArray=[4,2]))
    d.add(String(8, dh-18, "CYTOPLASM",
                 fontName='Helvetica-Bold', fontSize=8,
                 fillColor=CYTO_BORDER))

    # Re-draw mito on top
    d.add(Ellipse(cx, cy+18, mito_rx, mito_ry,
                  fillColor=MITO_COLOR, strokeColor=MITO_BORDER,
                  strokeWidth=2.5, strokeDashArray=[5,3]))

    # ── Helper functions ───────────────────────────────────────────────────────
    def node(x, y, text, lines2=None, fill=ROYAL_BLUE, tc=WHITE, w=90, h=28, r=8):
        d.add(Rect(x-w/2, y-h/2, w, h,
                   fillColor=fill, strokeColor=colors.white,
                   strokeWidth=1, rx=r, ry=r))
        d.add(String(x, y + (6 if not lines2 else 8), text,
                     fontName='Helvetica-Bold', fontSize=8.5,
                     fillColor=tc, textAnchor='middle'))
        if lines2:
            d.add(String(x, y-4, lines2,
                         fontName='Helvetica', fontSize=7,
                         fillColor=tc, textAnchor='middle'))

    def enzyme_tag(x, y, text, color=TEAL):
        words = text.split()
        mid = len(words)//2
        line1 = ' '.join(words[:mid])
        line2 = ' '.join(words[mid:])
        tw = max(len(line1), len(line2)) * 5.5 + 8
        d.add(Rect(x - tw/2, y-8, tw, 22,
                   fillColor=color, strokeColor=WHITE,
                   strokeWidth=0.5, rx=4, ry=4))
        if line2:
            d.add(String(x, y+7, line1, fontName='Helvetica-Oblique',
                         fontSize=6.8, fillColor=WHITE, textAnchor='middle'))
            d.add(String(x, y-1, line2, fontName='Helvetica-Oblique',
                         fontSize=6.8, fillColor=WHITE, textAnchor='middle'))
        else:
            d.add(String(x, y+3, text, fontName='Helvetica-Oblique',
                         fontSize=6.8, fillColor=WHITE, textAnchor='middle'))

    def side_label(x, y, text, color=ACCENT_GOLD):
        d.add(String(x, y, text, fontName='Helvetica', fontSize=7.5,
                     fillColor=color, textAnchor='middle'))

    def arrow(x1, y1, x2, y2, color=DARK_GRAY, w=1.8):
        dx, dy = x2-x1, y2-y1
        length = math.sqrt(dx*dx + dy*dy)
        if length == 0: return
        ux, uy = dx/length, dy/length
        # shaft
        d.add(Line(x1, y1, x2-ux*8, y2-uy*8,
                   strokeColor=color, strokeWidth=w))
        # arrowhead
        angle = math.atan2(uy, ux)
        al = 9
        aw2 = 4
        tip_x, tip_y = x2, y2
        left_x  = tip_x - al*math.cos(angle) + aw2*math.sin(angle)
        left_y  = tip_y - al*math.sin(angle) - aw2*math.cos(angle)
        right_x = tip_x - al*math.cos(angle) - aw2*math.sin(angle)
        right_y = tip_y - al*math.sin(angle) + aw2*math.cos(angle)
        d.add(Polygon([tip_x, tip_y, left_x, left_y, right_x, right_y],
                      fillColor=color, strokeColor=color, strokeWidth=0.5))

    # ── Node positions (clock face on a cycle) ────────────────────────────────
    # Mito nodes: NH3+CO2 (top-left in mito), Ornithine (bottom-left mito),
    #             Carbamoyl-P (top-center mito), Citrulline (right mito exit)
    n = {
        'orn_mito': (cx-95, cy+18),        # Ornithine enters mito (left)
        'cp':       (cx-30, cy+130),        # Carbamoyl phosphate (top mito)
        'cit_mito': (cx+100, cy+70),        # Citrulline (right mito)
        'cit_cyto': (cx+135, cy-30),        # Citrulline in cytoplasm
        'ass':      (cx+100, cy-130),       # Argininosuccinate
        'arg':      (cx-50, cy-155),        # Arginine
        'orn_cyto': (cx-140, cy-80),        # Ornithine cytoplasm
        'urea':     (cx-165, cy+18),        # Urea exits
    }

    # Input nodes (substrates)
    nh3_x, nh3_y = cx-105, cy+145
    asp_x, asp_y = cx+30, cy-185

    # ── Arrows between cycle intermediates ───────────────────────────────────
    # NH3 + CO2 → Carbamoyl-P
    arrow(nh3_x+38, nh3_y, n['cp'][0]-10, n['cp'][1]+6, ACCENT_GREEN)
    # Carbamoyl-P → Citrulline (mito)
    arrow(n['cp'][0]+48, n['cp'][1], n['cit_mito'][0]-42, n['cit_mito'][1]+28, DARK_GRAY)
    # Orn (mito) → Citrulline
    arrow(n['orn_mito'][0]+46, n['orn_mito'][1]+5, n['cit_mito'][0]-42, n['cit_mito'][1]-5, DARK_GRAY)
    # Citrulline exits mito into cytoplasm
    arrow(n['cit_mito'][0]+2, n['cit_mito'][1]-14, n['cit_cyto'][0]-2, n['cit_cyto'][1]+10, ACCENT_GOLD, 2)
    # Citrulline+Asp → Argininosuccinate
    arrow(n['cit_cyto'][0]-15, n['cit_cyto'][1]-15, n['ass'][0]+10, n['ass'][1]+14, DARK_GRAY)
    # Asp enters
    arrow(asp_x, asp_y+15, n['ass'][0]-5, n['ass'][1]+14, ACCENT_GREEN)
    # Argininosuccinate → Arginine
    arrow(n['ass'][0]-46, n['ass'][1]+4, n['arg'][0]+44, n['arg'][1]+4, DARK_GRAY)
    # Arginine → Ornithine + Urea
    arrow(n['arg'][0]-42, n['arg'][1], n['orn_cyto'][0]+44, n['orn_cyto'][1]+8, DARK_GRAY)
    # Ornithine (cyto) → Ornithine (mito) re-enters
    arrow(n['orn_cyto'][0]+20, n['orn_cyto'][1]+16, n['orn_mito'][0]-10, n['orn_mito'][1]-10, ACCENT_GOLD, 2)
    # Urea exits
    arrow(n['urea'][0]-10, n['urea'][1]+5, 32, n['urea'][1]+5, ACCENT_RED, 2)

    # Fumarate exits from Argininosuccinate lyase step
    arrow(n['arg'][0]+20, n['arg'][1]-14,
          n['arg'][0]+55, n['arg'][1]-55, ACCENT_PURP)

    # ── Metabolite nodes ──────────────────────────────────────────────────────
    # Substrates / inputs
    node(nh3_x, nh3_y, "NH₃ + CO₂", "2 ATP consumed",
         fill=ACCENT_GREEN, w=100, h=30)
    node(asp_x, asp_y, "Aspartate", "(2nd Nitrogen)",
         fill=ACCENT_GREEN, w=92, h=28)

    # Cycle intermediates
    node(n['cp'][0],       n['cp'][1],       "Carbamoyl", "Phosphate",
         fill=ROYAL_BLUE, w=86, h=30)
    node(n['cit_mito'][0], n['cit_mito'][1], "Citrulline", "(mito)",
         fill=ROYAL_BLUE, w=86, h=28)
    node(n['orn_mito'][0], n['orn_mito'][1], "Ornithine", "(mito)",
         fill=ROYAL_BLUE, w=86, h=28)
    node(n['cit_cyto'][0], n['cit_cyto'][1], "Citrulline", "(cytoplasm)",
         fill=TEAL, w=90, h=28)
    node(n['ass'][0],      n['ass'][1],      "Argino-", "succinate",
         fill=TEAL, w=88, h=30)
    node(n['arg'][0],      n['arg'][1],      "Arginine",
         fill=TEAL, w=82, h=28)
    node(n['orn_cyto'][0], n['orn_cyto'][1], "Ornithine", "(cytoplasm)",
         fill=TEAL, w=88, h=28)

    # Products
    node(n['urea'][0], n['urea'][1], "UREA",
         fill=ACCENT_RED, tc=WHITE, w=70, h=30)
    d.add(String(22, n['urea'][1]+5, "→ Urine",
                 fontName='Helvetica-Bold', fontSize=8,
                 fillColor=ACCENT_RED))

    # Fumarate label
    node(n['arg'][0]+72, n['arg'][1]-70, "Fumarate", "→ TCA cycle",
         fill=ACCENT_PURP, w=90, h=28)

    # ── Enzyme labels ─────────────────────────────────────────────────────────
    enzyme_tag(cx-72, cy+115, "CPS I", ACCENT_GREEN)
    enzyme_tag(cx+42, cy+110, "OTC", MITO_BORDER)
    enzyme_tag(cx+148, cy+20, "Antiporter", MITO_BORDER)
    enzyme_tag(cx+145, cy-90, "ASS", TEAL)
    enzyme_tag(cx+25,  cy-165, "ASL", TEAL)
    enzyme_tag(cx-110, cy-140, "Arginase I", ACCENT_RED)
    enzyme_tag(cx-175, cy-42, "Antiporter", MITO_BORDER)

    # ── Step numbers ──────────────────────────────────────────────────────────
    steps = [(cx-72, cy+138, "①"), (cx+42, cy+125, "②"),
             (cx+160, cy+6, "③"), (cx+145, cy-108, "④"),
             (cx+20, cy-178, "⑤"), (cx-108, cy-155, "⑥")]
    for sx, sy, st in steps:
        d.add(Circle(sx, sy, 8, fillColor=ACCENT_GOLD, strokeColor=WHITE,
                     strokeWidth=0.5))
        d.add(String(sx, sy-3, st,
                     fontName='Helvetica-Bold', fontSize=7,
                     fillColor=WHITE, textAnchor='middle'))

    # ── NAG note ──────────────────────────────────────────────────────────────
    d.add(Rect(cx-175, cy+145, 95, 30,
               fillColor=LIGHT_GOLD, strokeColor=ACCENT_GOLD,
               strokeWidth=1, rx=4, ry=4))
    d.add(String(cx-130, cy+167, "★ NAG activates CPS I",
                 fontName='Helvetica-Bold', fontSize=7,
                 fillColor=ACCENT_RED))
    d.add(String(cx-130, cy+154, "(Rate-limiting step)",
                 fontName='Helvetica', fontSize=6.5,
                 fillColor=DARK_GRAY))

    # ── ATP cost label ────────────────────────────────────────────────────────
    d.add(Rect(cx+30, cy+145, 115, 30,
               fillColor=LIGHT_RED, strokeColor=ACCENT_RED,
               strokeWidth=1, rx=4, ry=4))
    d.add(String(cx+88, cy+167, "4 ATP equivalents used",
                 fontName='Helvetica-Bold', fontSize=7,
                 fillColor=ACCENT_RED, textAnchor='middle'))
    d.add(String(cx+88, cy+154, "per urea synthesized",
                 fontName='Helvetica', fontSize=6.5,
                 fillColor=DARK_GRAY, textAnchor='middle'))

    return d

# ══════════════════════════════════════════════════════════════════════════════
#  DIAGRAM 2 – Transdeamination (Transamination + Oxidative Deamination)
# ══════════════════════════════════════════════════════════════════════════════
def draw_transdeamination(dw=480, dh=200):
    d = Drawing(dw, dh)
    y = dh / 2

    def box(x, cy, text, sub=None, fill=ROYAL_BLUE, tc=WHITE, w=95, h=34):
        d.add(Rect(x-w/2, cy-h/2, w, h,
                   fillColor=fill, strokeColor=WHITE, strokeWidth=1, rx=7, ry=7))
        d.add(String(x, cy+(7 if sub else 3), text,
                     fontName='Helvetica-Bold', fontSize=8.5,
                     fillColor=tc, textAnchor='middle'))
        if sub:
            d.add(String(x, cy-7, sub,
                         fontName='Helvetica', fontSize=7,
                         fillColor=tc, textAnchor='middle'))

    def arr(x1, y1, x2, y2, label='', lc=DARK_GRAY):
        d.add(Line(x1, y1, x2-8, y2,
                   strokeColor=DARK_GRAY, strokeWidth=1.8))
        d.add(Polygon([x2, y2, x2-10, y2+5, x2-10, y2-5],
                      fillColor=DARK_GRAY, strokeColor=DARK_GRAY))
        if label:
            d.add(String((x1+x2)/2, y2+9, label,
                         fontName='Helvetica-Oblique', fontSize=7.5,
                         fillColor=TEAL, textAnchor='middle'))

    def note(x, y, text, color=ACCENT_GOLD):
        d.add(String(x, y, text, fontName='Helvetica', fontSize=7,
                     fillColor=color, textAnchor='middle'))

    # Background panels
    d.add(Rect(2, 2, dw/2-5, dh-4,
               fillColor=LIGHT_BLUE, strokeColor=ROYAL_BLUE,
               strokeWidth=1, rx=6, ry=6))
    d.add(String(dw/4, dh-14, "Step 1: TRANSAMINATION",
                 fontName='Helvetica-Bold', fontSize=8,
                 fillColor=ROYAL_BLUE, textAnchor='middle'))

    d.add(Rect(dw/2+3, 2, dw/2-5, dh-4,
               fillColor=LIGHT_GREEN, strokeColor=ACCENT_GREEN,
               strokeWidth=1, rx=6, ry=6))
    d.add(String(3*dw/4, dh-14, "Step 2: OXIDATIVE DEAMINATION",
                 fontName='Helvetica-Bold', fontSize=8,
                 fillColor=ACCENT_GREEN, textAnchor='middle'))

    # Step 1 boxes
    box(55,  y, "Amino Acid", "(e.g., Alanine)", ROYAL_BLUE)
    arr(108, y, 148, y, "")
    box(195, y, "α-Keto Acid", "(e.g., Pyruvate)", TEAL)
    note(150, y+22, "α-KG")
    note(150, y+12, "↕")
    note(150, y+2, "Glutamate")
    note(52, y-28, "Enzyme: Aminotransferase")
    note(52, y-38, "Coenzyme: PLP (Vit B6)")

    # Separator arrow to step 2
    arr(235, y, 270, y, "")

    # Step 2 boxes
    box(310, y, "Glutamate", fill=ACCENT_GREEN)
    arr(360, y, 396, y, "GDH")
    box(435, y, "α-KG +", "Free NH₃", ACCENT_RED)

    note(310, y-25, "NAD⁺ → NADH")
    note(435, y-28, "★ Free NH₃ released")
    note(435, y-38, "→ enters urea cycle")

    # Regulation note
    d.add(Rect(dw/2+8, 10, 100, 32,
               fillColor=LIGHT_GOLD, strokeColor=ACCENT_GOLD,
               strokeWidth=0.8, rx=4, ry=4))
    d.add(String(dw/2+58, 33, "GTP ⛔ Inhibits GDH",
                 fontName='Helvetica', fontSize=6.5,
                 fillColor=DARK_GRAY, textAnchor='middle'))
    d.add(String(dw/2+58, 20, "ADP ✅ Activates GDH",
                 fontName='Helvetica', fontSize=6.5,
                 fillColor=DARK_GRAY, textAnchor='middle'))

    return d

# ══════════════════════════════════════════════════════════════════════════════
#  DIAGRAM 3 – Ammonia Transport (Glucose-Alanine Cycle)
# ══════════════════════════════════════════════════════════════════════════════
def draw_alanine_cycle(dw=480, dh=210):
    d = Drawing(dw, dh)

    def box(x, y, text, sub=None, fill=ROYAL_BLUE, tc=WHITE, w=100, h=32):
        d.add(Rect(x-w/2, y-h/2, w, h,
                   fillColor=fill, strokeColor=WHITE, strokeWidth=1, rx=7, ry=7))
        d.add(String(x, y+(6 if sub else 2), text,
                     fontName='Helvetica-Bold', fontSize=8.5,
                     fillColor=tc, textAnchor='middle'))
        if sub:
            d.add(String(x, y-8, sub, fontName='Helvetica', fontSize=7,
                         fillColor=tc, textAnchor='middle'))

    def arr(x1, y1, x2, y2, label='', color=DARK_GRAY, above=True):
        d.add(Line(x1, y1, x2-9, y2, strokeColor=color, strokeWidth=1.8))
        d.add(Polygon([x2, y2, x2-11, y2+5, x2-11, y2-5],
                      fillColor=color, strokeColor=color))
        if label:
            ly = (y1+y2)/2 + (10 if above else -12)
            d.add(String((x1+x2)/2, ly, label,
                         fontName='Helvetica-Oblique', fontSize=7.5,
                         fillColor=TEAL, textAnchor='middle'))

    def label(x, y, text, color=DARK_GRAY, bold=False):
        fn = 'Helvetica-Bold' if bold else 'Helvetica'
        d.add(String(x, y, text, fontName=fn, fontSize=7.5,
                     fillColor=color, textAnchor='middle'))

    # Background panels
    d.add(Rect(4, 4, dw/2-10, dh-8,
               fillColor=LIGHT_BLUE, strokeColor=ROYAL_BLUE,
               strokeWidth=1.2, rx=6, ry=6))
    label(dw/4, dh-14, "MUSCLE", ROYAL_BLUE, bold=True)

    d.add(Rect(dw/2+6, 4, dw/2-10, dh-8,
               fillColor=LIGHT_GREEN, strokeColor=ACCENT_GREEN,
               strokeWidth=1.2, rx=6, ry=6))
    label(3*dw/4, dh-14, "LIVER", ACCENT_GREEN, bold=True)

    # Muscle side
    box(90, 155, "Pyruvate", fill=TEAL)
    box(90, 85,  "Alanine",  fill=ROYAL_BLUE)
    label(90, 120, "ALT + NH₃", DARK_GRAY)
    arr(90, 138, 90, 102, "", ROYAL_BLUE)

    # Transport arrow
    arr(148, 85, 330, 85, "Blood transport", ACCENT_GOLD)

    # Liver side
    box(382, 85,  "Alanine", fill=ROYAL_BLUE)
    box(382, 155, "Pyruvate", fill=TEAL)
    label(382, 120, "ALT releases NH₃", DARK_GRAY)
    arr(382, 102, 382, 138, "", TEAL)

    # NH3 → urea cycle
    box(460, 155, "NH₃", "→ Urea Cycle", ACCENT_RED, w=90)
    arr(428, 155, 414, 155, "", ACCENT_RED)

    # Glucose return
    box(382, 30, "Glucose", "Gluconeogenesis", ACCENT_GREEN)
    arr(382, 138, 382, 46, "", ACCENT_GREEN)
    arr(330, 30, 148, 30, "Glucose → Muscle", ACCENT_GREEN)
    arr(90, 46, 90, 68, "", ACCENT_GREEN)

    label(240, 68, "★ Glucose-Alanine Cycle", ACCENT_RED, bold=True)

    return d

# ══════════════════════════════════════════════════════════════════════════════
#  DIAGRAM 4 – Protein Digestion Flow
# ══════════════════════════════════════════════════════════════════════════════
def draw_digestion(dw=480, dh=170):
    d = Drawing(dw, dh)

    stages = [
        ("STOMACH", "HCl + Pepsin\nDenatures & cleaves\n→ Polypeptides", ROYAL_BLUE, 60),
        ("PANCREAS", "Trypsin, Chymotrypsin\nElastase, Carboxypeptidase\n→ Oligopeptides + AAs", TEAL, 180),
        ("BRUSH BORDER", "Aminopeptidase\n→ Di/tripeptides + AAs", ACCENT_PURP, 300),
        ("ABSORPTION", "Na⁺-linked (free AAs)\nH⁺-linked (di/tri)\n→ Portal blood", ACCENT_GREEN, 420),
    ]

    for name, detail, color, x in stages:
        bh = 100
        d.add(Rect(x-55, dh-bh-20, 110, bh,
                   fillColor=color, strokeColor=WHITE, strokeWidth=1, rx=8, ry=8))
        d.add(String(x, dh-25, name,
                     fontName='Helvetica-Bold', fontSize=8,
                     fillColor=WHITE, textAnchor='middle'))
        lines = detail.split('\n')
        for i, line in enumerate(lines):
            d.add(String(x, dh-42-i*16, line,
                         fontName='Helvetica', fontSize=7.5,
                         fillColor=WHITE, textAnchor='middle'))
        if x < 420:
            d.add(Polygon([x+60, dh-68, x+70, dh-62, x+60, dh-56],
                          fillColor=ACCENT_GOLD, strokeColor=ACCENT_GOLD))

    # Activation cascade note
    d.add(Rect(120, 2, 240, 18,
               fillColor=LIGHT_GOLD, strokeColor=ACCENT_GOLD,
               strokeWidth=0.8, rx=3, ry=3))
    d.add(String(240, 7, "★ Enteropeptidase → Trypsin → activates all other zymogens",
                 fontName='Helvetica-Bold', fontSize=6.5,
                 fillColor=ACCENT_RED, textAnchor='middle'))

    return d

# ══════════════════════════════════════════════════════════════════════════════
#  DIAGRAM 5 – Hyperammonemia Types & Treatment
# ══════════════════════════════════════════════════════════════════════════════
def draw_hyperammonemia(dw=480, dh=190):
    d = Drawing(dw, dh)

    # Central circle
    d.add(Circle(240, 100, 55,
                 fillColor=ACCENT_RED, strokeColor=WHITE, strokeWidth=2))
    d.add(String(240, 112, "HYPER-",
                 fontName='Helvetica-Bold', fontSize=10,
                 fillColor=WHITE, textAnchor='middle'))
    d.add(String(240, 98, "AMMONEMIA",
                 fontName='Helvetica-Bold', fontSize=10,
                 fillColor=WHITE, textAnchor='middle'))
    d.add(String(240, 82, ">35 µmol/L",
                 fontName='Helvetica', fontSize=8,
                 fillColor=LIGHT_RED, textAnchor='middle'))

    def side_box(x, y, title, lines, fill, border):
        h = len(lines)*14 + 22
        w = 155
        d.add(Rect(x, y-h/2, w, h,
                   fillColor=fill, strokeColor=border,
                   strokeWidth=1.2, rx=6, ry=6))
        d.add(String(x+w/2, y+h/2-14, title,
                     fontName='Helvetica-Bold', fontSize=8,
                     fillColor=border, textAnchor='middle'))
        for i, line in enumerate(lines):
            d.add(String(x+8, y+h/2-26-i*14, line,
                         fontName='Helvetica', fontSize=7.2,
                         fillColor=DARK_GRAY))

    # Acquired (left)
    side_box(8, 105, "ACQUIRED (Adults)",
             ["• Liver disease (hepatitis/cirrhosis)",
              "• Portal-systemic shunting",
              "• Impaired urea cycle"],
             LIGHT_RED, ACCENT_RED)
    d.add(Line(163, 105, 186, 105, strokeColor=ACCENT_RED, strokeWidth=1.5))
    d.add(Polygon([186,105,178,109,178,101],
                  fillColor=ACCENT_RED, strokeColor=ACCENT_RED))

    # Congenital (right)
    side_box(318, 105, "CONGENITAL (Newborns)",
             ["• OTC deficiency (X-linked) ← most common",
              "• CPS I, ASS, ASL deficiencies (AR)",
              "• Arginine becomes essential AA"],
             LIGHT_GOLD, ACCENT_GOLD)
    d.add(Line(294, 105, 318, 105, strokeColor=ACCENT_GOLD, strokeWidth=1.5))
    d.add(Polygon([318,105,310,109,310,101],
                  fillColor=ACCENT_GOLD, strokeColor=ACCENT_GOLD))

    # Treatment (bottom)
    tx_items = [
        "① Protein restriction + adequate calories",
        "② Phenylbutyrate → exports 2 N as phenylacetylglutamine",
        "③ Na-benzoate → exports 1 N as hippurate",
        "④ Neomycin/lactulose → ↓ gut NH₃",
        "⑤ Arginine/citrulline supplementation",
        "⑥ Liver transplant (definitive cure)",
    ]
    tx_h = len(tx_items)*13 + 18
    d.add(Rect(4, 2, dw-8, tx_h-2,
               fillColor=LIGHT_GREEN, strokeColor=ACCENT_GREEN,
               strokeWidth=1, rx=5, ry=5))
    d.add(String(dw/2, tx_h-4, "TREATMENT STRATEGIES",
                 fontName='Helvetica-Bold', fontSize=8,
                 fillColor=ACCENT_GREEN, textAnchor='middle'))
    for i, item in enumerate(tx_items):
        d.add(String(12, tx_h-16-i*13, item,
                     fontName='Helvetica', fontSize=7,
                     fillColor=DARK_GRAY))

    return d

# ══════════════════════════════════════════════════════════════════════════════
#  TABLE helpers
# ══════════════════════════════════════════════════════════════════════════════
def styled_table(data, col_widths, header_bg=ROYAL_BLUE):
    t = Table(data, colWidths=col_widths)
    style = TableStyle([
        ('BACKGROUND',   (0,0), (-1,0), header_bg),
        ('TEXTCOLOR',    (0,0), (-1,0), WHITE),
        ('FONTNAME',     (0,0), (-1,0), 'Helvetica-Bold'),
        ('FONTSIZE',     (0,0), (-1,0), 9),
        ('ALIGN',        (0,0), (-1,0), 'CENTER'),
        ('ROWBACKGROUNDS',(0,1),(-1,-1),[WHITE, LIGHT_GRAY]),
        ('FONTNAME',     (0,1), (-1,-1),'Helvetica'),
        ('FONTSIZE',     (0,1), (-1,-1), 8.5),
        ('TOPPADDING',   (0,0), (-1,-1), 5),
        ('BOTTOMPADDING',(0,0), (-1,-1), 5),
        ('LEFTPADDING',  (0,0), (-1,-1), 7),
        ('GRID',         (0,0), (-1,-1), 0.4, colors.HexColor("#CCCCCC")),
        ('ROWBACKGROUNDS',(0,1),(-1,-1),[WHITE, LIGHT_BLUE]),
        ('VALIGN',       (0,0), (-1,-1), 'MIDDLE'),
    ])
    t.setStyle(style)
    return t

def section_header(text, bg=ROYAL_BLUE):
    return SectionBanner(text, bg=bg, w=W-3*cm)

# ══════════════════════════════════════════════════════════════════════════════
#  COVER PAGE
# ══════════════════════════════════════════════════════════════════════════════
class CoverPage(Flowable):
    def __init__(self, w=W, h=H):
        super().__init__()
        self._w = w
        self._h = h
    def wrap(self, aw, ah): return self._w, self._h
    def draw(self):
        c = self.canv
        # Deep gradient background
        c.setFillColor(DEEP_NAVY)
        c.rect(0, 0, self._w, self._h, fill=1, stroke=0)
        # Accent band
        c.setFillColor(ROYAL_BLUE)
        c.rect(0, self._h*0.38, self._w, self._h*0.28, fill=1, stroke=0)
        # Top accent line
        c.setFillColor(ACCENT_GOLD)
        c.rect(0, self._h*0.66+2, self._w, 4, fill=1, stroke=0)
        c.rect(0, self._h*0.38-2, self._w, 4, fill=1, stroke=0)

        # DNA helix decoration (simple circles)
        import random
        random.seed(42)
        for i in range(18):
            x = self._w*0.88 + 10*math.sin(i*0.7)
            y = self._h*0.1 + i*30
            r = 6+3*abs(math.sin(i*0.7))
            c.setFillColor(colors.HexColor("#1B4F8A"))
            c.circle(x, y, r, fill=1, stroke=0)

        # Title text
        c.setFillColor(WHITE)
        c.setFont('Helvetica-Bold', 30)
        c.drawCentredString(self._w/2, self._h*0.72, "Amino Acids:")
        c.setFont('Helvetica-Bold', 30)
        c.drawCentredString(self._w/2, self._h*0.66+12, "Disposal of Nitrogen")

        c.setFillColor(LIGHT_BLUE)
        c.setFont('Helvetica', 14)
        c.drawCentredString(self._w/2, self._h*0.62, "Chapter 19 — Lippincott's Illustrated Reviews: Biochemistry")

        # Chapter tags
        tags = ["Urea Cycle", "Transdeamination", "Hyperammonemia",
                "Protein Digestion", "Ammonia Transport", "Nitrogen Balance"]
        tag_x = 60
        for tag in tags:
            tw = len(tag)*7 + 16
            c.setFillColor(TEAL)
            c.roundRect(tag_x, self._h*0.56, tw, 18, 4, fill=1, stroke=0)
            c.setFillColor(WHITE)
            c.setFont('Helvetica', 8)
            c.drawString(tag_x+8, self._h*0.56+5, tag)
            tag_x += tw + 8

        # Author/source
        c.setFillColor(ACCENT_GOLD)
        c.setFont('Helvetica-Bold', 10)
        c.drawCentredString(self._w/2, self._h*0.34, "Comprehensive Study Guide with Diagrams")
        c.setFillColor(MID_GRAY)
        c.setFont('Helvetica', 9)
        c.drawCentredString(self._w/2, self._h*0.30, "Based on Lippincott's Biochemistry, Chapter 19")

        # Bottom bar
        c.setFillColor(ACCENT_GOLD)
        c.rect(0, 0, self._w, 30, fill=1, stroke=0)
        c.setFillColor(DEEP_NAVY)
        c.setFont('Helvetica-Bold', 9)
        c.drawCentredString(self._w/2, 10, "Biochemistry  •  Amino Acid Metabolism  •  Nitrogen Disposal")


# ══════════════════════════════════════════════════════════════════════════════
#  BUILD THE PDF
# ══════════════════════════════════════════════════════════════════════════════
OUTPUT = "/home/daytona/workspace/nitrogen-study-guide/Amino_Acids_Nitrogen_Disposal_Study_Guide.pdf"

def build_pdf():
    doc = SimpleDocTemplate(
        OUTPUT,
        pagesize=A4,
        leftMargin=1.5*cm, rightMargin=1.5*cm,
        topMargin=1.5*cm, bottomMargin=1.5*cm,
        title="Amino Acids: Disposal of Nitrogen — Study Guide",
        author="Lippincott's Biochemistry Ch.19",
    )

    story = []
    S = Spacer(1, 0.3*cm)
    SM = Spacer(1, 0.5*cm)
    LG = Spacer(1, 0.8*cm)

    # ── COVER ──────────────────────────────────────────────────────────────────
    story.append(CoverPage())
    story.append(PageBreak())

    # ── TABLE OF CONTENTS ──────────────────────────────────────────────────────
    story.append(section_header("📋  TABLE OF CONTENTS"))
    story.append(SM)
    toc_data = [
        ["#", "Section", "Page"],
        ["1", "Overview & Big Picture", "3"],
        ["2", "Amino Acid Pool & Protein Turnover", "3"],
        ["3", "Protein Digestion (with Diagram)", "4"],
        ["4", "Amino Acid Transport & Genetic Disorders", "4"],
        ["5", "Removal of Nitrogen: Transdeamination (with Diagram)", "5"],
        ["6", "Ammonia Transport: Glutamine & Glucose-Alanine Cycle", "6"],
        ["7", "THE UREA CYCLE — Full Diagram + Steps", "7"],
        ["8", "Urea Cycle Stoichiometry & Regulation", "8"],
        ["9", "Hyperammonemia: Types & Treatment (with Diagram)", "9"],
        ["10", "High-Yield Summary Tables", "10"],
        ["11", "Exam One-Liners & Memory Tricks", "11"],
    ]
    story.append(styled_table(toc_data, [0.7*cm, 11*cm, 1.8*cm]))
    story.append(PageBreak())

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 1 — OVERVIEW
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("1 ·  Overview & The Big Picture", DEEP_NAVY))
    story.append(SM)
    story.append(Paragraph(
        b("Core principle:") + " Amino acids cannot be stored. Excess amino acids are degraded — "
        "nitrogen is stripped off (toxic as ammonia) and converted to urea for excretion; "
        "carbon skeletons enter central metabolic pathways.",
        highlight))
    story.append(S)
    story.append(Paragraph(b("Two phases of amino acid catabolism:"), h3))
    story.append(bullet(b("Phase 1 — Nitrogen removal:") + " α-amino group removed → free NH₃ + α-keto acid. NH₃ → converted to urea (main route)."))
    story.append(bullet(b("Phase 2 — Carbon skeleton fate:") + " α-keto acid enters TCA cycle, gluconeogenesis, fatty acid synthesis, or ketogenesis."))
    story.append(S)
    story.append(Paragraph(b("Nitrogen balance:"), h3))
    story.append(bullet("Healthy adults: N input = N output (zero balance)"))
    story.append(bullet("Positive balance: growth, pregnancy, recovery from illness"))
    story.append(bullet("Negative balance: starvation, severe illness, muscle wasting"))
    story.append(SM)

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 2 — AMINO ACID POOL & TURNOVER
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("2 ·  Amino Acid Pool & Protein Turnover", ROYAL_BLUE))
    story.append(SM)

    pool_data = [
        ["Fills the Pool", "Drains the Pool"],
        ["Dietary protein digestion & absorption", "Protein synthesis"],
        ["Body protein breakdown (turnover)", "Biosynthesis of N-containing compounds\n(purines, heme, creatine)"],
        ["Synthesis of nonessential amino acids", "Energy production (oxidation)"],
    ]
    story.append(styled_table(pool_data, [8*cm, 8*cm]))
    story.append(S)
    story.append(Paragraph(
        b("Protein turnover:") + " ~300–400 g of protein hydrolyzed and resynthesized DAILY. "
        "Regulatory proteins (enzymes, transcription factors) are short-lived (minutes–hours). "
        "Structural proteins (collagen, muscle) are long-lived (days–years).",
        body))
    story.append(S)
    story.append(Paragraph(b("Two protein degradation systems:"), h3))
    deg_data = [
        ["System", "Energy", "Mechanism", "Targets"],
        ["Ubiquitin-Proteasome", "ATP-dependent", "Proteins tagged with ubiquitin\n→ fed into proteasome barrel", "Intracellular proteins;\nPEST-sequence proteins (fast)"],
        ["Lysosomal Degradation", "ATP-independent", "Acid hydrolases (cathepsins)\ndegrade engulfed material", "Extracellular/membrane proteins;\nautophagocytosed organelles"],
    ]
    story.append(styled_table(deg_data, [3.5*cm, 2.8*cm, 5*cm, 5*cm]))
    story.append(PageBreak())

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 3 — PROTEIN DIGESTION
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("3 ·  Protein Digestion", TEAL))
    story.append(SM)
    story.append(Paragraph("Figure 1 — Protein Digestion Pipeline (Stomach → Absorption)", caption))
    story.append(S)
    story.append(draw_digestion())
    story.append(S)
    story.append(Paragraph("Caption: Proteins are digested sequentially by three stations. All pancreatic enzymes are secreted as "
                           "inactive zymogens; enteropeptidase triggers the activation cascade by activating trypsinogen → trypsin, "
                           "which then activates all others.", caption))
    story.append(SM)

    dig_data = [
        ["Location", "Enzyme/Agent", "Type", "Action"],
        ["Stomach (Parietal cells)", "HCl", "Acid", "Denatures proteins; activates pepsinogen"],
        ["Stomach (Chief cells)", "Pepsin", "Endopeptidase", "Cleaves large proteins → polypeptides (active at pH 1–2)"],
        ["Pancreas", "Trypsin", "Endopeptidase", "Cleaves after Arg, Lys"],
        ["Pancreas", "Chymotrypsin", "Endopeptidase", "Cleaves after Phe, Tyr, Trp"],
        ["Pancreas", "Elastase", "Endopeptidase", "Cleaves after small neutral AAs"],
        ["Pancreas", "Carboxypeptidases A/B", "Exopeptidase", "Cleaves C-terminal amino acids"],
        ["Brush border", "Aminopeptidase", "Exopeptidase", "Cleaves N-terminal amino acids"],
        ["Enterocytes", "Intracellular peptidases", "Hydrolase", "Hydrolyze di/tripeptides → free AAs"],
    ]
    story.append(styled_table(dig_data, [3.5*cm, 4*cm, 2.8*cm, 5.4*cm]))
    story.append(S)
    story.append(Paragraph(
        b("Absorption:") + " Free AAs → Na⁺-coupled transport. Di/tripeptides → H⁺-coupled (PepT1) → hydrolyzed inside "
        "enterocyte. Only free AAs enter portal blood. " +
        b("Exception:") + " Branched-chain AAs (Val, Leu, Ile) bypass liver and go directly to muscle.",
        body))
    story.append(SM)

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 4 — TRANSPORT & GENETIC DISORDERS
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("4 ·  Amino Acid Transport & Genetic Disorders", ACCENT_PURP))
    story.append(SM)
    story.append(Paragraph(
        "Intracellular [AA] > extracellular [AA] → maintained by active transport (at least 7 transport systems). "
        "The same systems are shared between the intestinal brush border and the renal proximal tubule, so a "
        "single defect causes both malabsorption and aminoaciduria.",
        body))
    story.append(S)
    disorder_data = [
        ["Disorder", "Defect", "Amino Acids Affected", "Consequence"],
        ["Cystinuria", "COAL transport system", "Cystine, Ornithine,\nArginine, Lysine",
         "Kidney stones (cystine precipitates at normal urine pH).\nMost common AA transport disorder (1:7,000)"],
        ["Hartnup Disease", "Neutral AA transporter\n(SLC6A19)", "Tryptophan (main)\n+ other neutral AAs",
         "↓ Tryptophan → ↓ Niacin synthesis → pellagra-like:\ndermatitis, diarrhea, dementia"],
    ]
    story.append(styled_table(disorder_data, [2.8*cm, 3.2*cm, 3.5*cm, 6.7*cm]))
    story.append(PageBreak())

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 5 — TRANSDEAMINATION
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("5 ·  Removal of Nitrogen: Transdeamination", ROYAL_BLUE))
    story.append(SM)
    story.append(Paragraph("Figure 2 — Transdeamination: Transamination + Oxidative Deamination", caption))
    story.append(S)
    story.append(draw_transdeamination())
    story.append(S)
    story.append(Paragraph(
        "Caption: Step 1 (transamination) funnels nitrogen from most amino acids onto α-ketoglutarate, producing "
        "glutamate — the central nitrogen collector. Step 2 (oxidative deamination by GDH) releases free NH₃ "
        "from glutamate for the urea cycle.", caption))
    story.append(SM)

    story.append(Paragraph(b("Step 1 — Transamination (the nitrogen funnel)"), h2))
    story.append(bullet("Most amino acids transfer their α-amino group to " + b("α-ketoglutarate") + " → " + b("Glutamate") + " + α-keto acid"))
    story.append(bullet("Enzyme: " + b("Aminotransferases (transaminases)") + " — coenzyme: " + b("PLP (pyridoxal phosphate)") + " from Vitamin B6"))
    story.append(bullet("PLP is covalently bound to a lysine residue at the active site (Schiff base linkage)"))
    story.append(bullet("Equilibrium ~1 → " + b("fully reversible") + ": functions in both catabolism (after meals) and anabolism (synthesis)"))
    story.append(bullet(b("Exceptions:") + " Lysine and Threonine do NOT undergo transamination"))
    story.append(S)

    trans_data = [
        ["Enzyme", "Reaction", "Location", "Clinical Significance"],
        ["ALT\n(Alanine aminotransferase)", "Alanine + α-KG ⇌\nPyruvate + Glutamate",
         "Liver (high), also\nmuscle, kidney", "Elevated in hepatocellular damage;\nmore liver-specific than AST"],
        ["AST\n(Aspartate aminotransferase)", "Glutamate + OAA ⇌\nAspartate + α-KG",
         "Heart, liver,\nmuscle, RBCs", "Elevated in MI, liver disease,\nmyopathies"],
    ]
    story.append(styled_table(trans_data, [3.5*cm, 4.5*cm, 3.5*cm, 4.7*cm]))
    story.append(S)

    story.append(Paragraph(b("Clinical: Elevated plasma ALT/AST = tissue damage"), h3))
    elevate_data = [
        ["Condition", "ALT", "AST", "Notes"],
        ["Viral hepatitis", "↑↑↑", "↑↑", "ALT > AST typical"],
        ["Alcoholic liver disease", "↑", "↑↑", "AST:ALT ratio > 2:1"],
        ["Drug/toxin liver injury", "↑↑↑", "↑↑↑", "Can be massive elevation"],
        ["Myocardial infarction", "Normal", "↑↑", "Also ↑ troponin, CK-MB"],
        ["Muscle disorders", "Mild ↑", "↑↑", "Also ↑ CK"],
    ]
    story.append(styled_table(elevate_data, [5*cm, 2*cm, 2*cm, 7.2*cm]))
    story.append(S)

    story.append(Paragraph(b("Step 2 — Oxidative Deamination (GDH)"), h2))
    story.append(bullet(b("Glutamate Dehydrogenase (GDH)") + " — liver/kidney mitochondria"))
    story.append(bullet("Glutamate + NAD⁺ → α-ketoglutarate + " + b("free NH₃") + " + NADH"))
    story.append(bullet("Dual coenzymes: NAD⁺ for deamination (catabolism); NADP⁺ for reductive amination (anabolism)"))
    story.append(bullet(b("Allosteric regulation:") + " GTP ⛔ inhibits (energy-rich) | ADP ✅ activates (energy-poor)"))
    story.append(S)
    story.append(Paragraph(b("D-Amino Acid Oxidase (DAO):") + " FAD-dependent, peroxisomal. Oxidizes dietary D-amino acids → α-keto acid + NH₃ + H₂O₂. "
        "Also degrades D-serine (NMDA receptor modulator) — altered DAO activity linked to schizophrenia.", body))
    story.append(PageBreak())

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 6 — AMMONIA TRANSPORT
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("6 ·  Ammonia Transport to the Liver", TEAL))
    story.append(SM)
    story.append(Paragraph(
        "Free NH₃ is neurotoxic even at low concentrations. Peripheral tissues package nitrogen into "
        "non-toxic carriers for safe transport to the liver.",
        body))
    story.append(S)
    story.append(Paragraph("Figure 3 — Glucose-Alanine Cycle (Muscle-Liver Axis)", caption))
    story.append(S)
    story.append(draw_alanine_cycle())
    story.append(S)
    story.append(Paragraph(
        "Caption: In muscle, pyruvate accepts nitrogen (via ALT) to form alanine, which travels to the liver. "
        "There, ALT reverses the reaction — releasing NH₃ for the urea cycle and pyruvate for gluconeogenesis. "
        "The resulting glucose returns to muscle, completing the cycle.", caption))
    story.append(SM)

    transport_data = [
        ["Carrier", "Tissues", "Formation", "Fate in Liver"],
        ["Glutamine\n(main carrier)", "All tissues\n(esp. brain, muscle)", "Glutamine synthetase (ATP):\nNH₃ + Glutamate → Glutamine",
         "Glutaminase:\nGlutamine → Glu + NH₃\n→ urea synthesis"],
        ["Alanine\n(muscle-specific)", "Skeletal muscle", "ALT: Pyruvate + Glu → Alanine\n(packages muscle NH₃)",
         "ALT (reversed): Alanine → Pyruvate\nPyruvate → glucose (gluconeogenesis)"],
    ]
    story.append(styled_table(transport_data, [2.8*cm, 3.2*cm, 5.5*cm, 4.7*cm]))
    story.append(PageBreak())

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 7 — UREA CYCLE
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("7 ·  THE UREA CYCLE", DEEP_NAVY))
    story.append(SM)
    story.append(Paragraph(
        b("Overview:") + " Urea = primary nitrogen disposal form in humans (~90% of urinary nitrogen). "
        "Each urea molecule carries 2 nitrogen atoms: 1 from free NH₃ (GDH) and 1 from aspartate (AST). "
        "Occurs in hepatocytes (mitochondria + cytoplasm). Urea → blood → kidneys → urine.",
        highlight))
    story.append(SM)
    story.append(Paragraph("Figure 4 — Complete Urea Cycle Diagram", caption))
    story.append(S)
    story.append(draw_urea_cycle(dw=int(W-3*cm), dh=470))
    story.append(S)
    story.append(Paragraph(
        "Caption: Numbered steps ① – ⑥ show the sequential reactions. Yellow background = mitochondrial reactions (Steps ①②); "
        "blue-green background = cytoplasmic reactions (Steps ③④⑤). Ornithine antiporter (③ transition) shuttles "
        "citrulline out and ornithine back in. Fumarate exits to the TCA cycle, linking the two pathways.",
        caption))
    story.append(PageBreak())

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 8 — STEPS, STOICHIOMETRY, REGULATION
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("8 ·  Urea Cycle Steps, Stoichiometry & Regulation", ROYAL_BLUE))
    story.append(SM)

    steps_data = [
        ["Step", "Location", "Substrate(s)", "Enzyme", "Product(s)", "Key Notes"],
        ["①", "Mitochondria", "NH₃ + CO₂\n+ 2 ATP", "CPS I\n(Carbamoyl\nPhosphate\nSynthetase I)",
         "Carbamoyl\nPhosphate + 2 ADP", "★ RATE-LIMITING STEP\nActivated by N-acetylglutamate (NAG)\nNAG is essential allosteric activator"],
        ["②", "Mitochondria", "Carbamoyl-P\n+ Ornithine", "OTC\n(Ornithine\nTranscarbamoylase)",
         "Citrulline + Pi", "Most common urea cycle disorder\nis OTC deficiency (X-linked)"],
        ["—", "Membrane", "Citrulline\n(mito → cyto)", "Ornithine/\nCitrulline\nAntiporter",
         "Citrulline\nin cytoplasm", "Ornithine re-enters mito in exchange"],
        ["③", "Cytoplasm", "Citrulline\n+ Aspartate\n+ ATP", "Argininosuccinate\nSynthetase (ASS)",
         "Argininosuccinate\n+ AMP + PPi", "★ SECOND NITROGEN enters here\n(from aspartate)\n1 ATP used → AMP (= 2 bonds)"],
        ["④", "Cytoplasm", "Argininosuccinate", "Argininosuccinate\nLyase (ASL)",
         "Arginine\n+ Fumarate", "Fumarate → TCA cycle (malate → OAA)\nLinks urea cycle to TCA"],
        ["⑤", "Cytoplasm", "Arginine\n+ H₂O", "Arginase I",
         "Urea\n+ Ornithine", "★ Arginase I exclusive to liver\nOrnithine recycled back to mito"],
    ]
    story.append(styled_table(steps_data, [1*cm, 2.2*cm, 2.5*cm, 3*cm, 2.5*cm, 5*cm]))
    story.append(SM)

    story.append(Paragraph(b("Stoichiometry:"), h2))
    story.append(KeyBox([
        "Aspartate + NH₃ + CO₂ + 3 ATP + H₂O  →  Urea + Fumarate + 2 ADP + AMP + 2 Pi + PPi",
        "★ 4 high-energy phosphate bonds consumed per urea molecule (counts PPi hydrolysis)",
        "★ Reaction is IRREVERSIBLE — large negative ΔG",
        "★ Both nitrogens of urea ultimately derive from GLUTAMATE",
    ], bg=LIGHT_BLUE, border=ROYAL_BLUE))
    story.append(SM)

    story.append(Paragraph(b("Regulation:"), h2))
    story.append(bullet(b("Rate-limiting enzyme:") + " CPS I — activated by N-acetylglutamate (NAG)"))
    story.append(bullet(b("NAG synthesis:") + " NAGS enzyme: Acetyl-CoA + Glutamate → NAG; Arginine activates NAGS (positive feedback)"))
    story.append(bullet(b("Short-term:") + " Substrate availability (more protein → more NH₃ → more NAG → more CPS I activity)"))
    story.append(bullet(b("Long-term:") + " High-protein diet induces transcription of urea cycle enzyme genes"))
    story.append(SM)

    story.append(Paragraph(b("Fate of Urea:"), h2))
    story.append(bullet("Diffuses from liver → blood → kidneys → filtered and excreted in urine (main route)"))
    story.append(bullet("~25% diffuses into intestine → gut bacteria urease → CO₂ + NH₃"))
    story.append(bullet(b("Renal failure:") + " elevated plasma urea drives more urea into gut → more bacterial NH₃ → worsens hyperammonemia"))
    story.append(bullet(b("Treatment:") + " oral neomycin (antibiotic reduces gut bacteria) or lactulose (acidifies colon, traps NH₄⁺)"))
    story.append(PageBreak())

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 9 — HYPERAMMONEMIA
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("9 ·  Hyperammonemia: Types & Treatment", ACCENT_RED))
    story.append(SM)
    story.append(Paragraph("Figure 5 — Hyperammonemia: Types & Treatment Overview", caption))
    story.append(S)
    story.append(draw_hyperammonemia(dw=int(W-3*cm), dh=200))
    story.append(SM)

    story.append(Paragraph(b("Normal plasma NH₃: 5–35 µmol/L  |  Emergency threshold: ~1000 µmol/L"), alert))
    story.append(S)

    story.append(Paragraph(b("Mechanism of CNS toxicity:"), h3))
    story.append(bullet("NH₃ depletes α-ketoglutarate (TCA intermediate) → impairs brain energy metabolism"))
    story.append(bullet("Excess glutamine synthesis in astrocytes → osmotic swelling → " + b("cerebral edema")))
    story.append(bullet("Direct neuronal membrane depolarization and impaired neurotransmitter balance"))
    story.append(S)

    story.append(Paragraph(b("Symptom progression (in order of severity):"), h3))
    story.append(Paragraph(
        "Tremors → Vomiting → Slurred speech → Asterixis (flapping tremor) → "
        "Encephalopathy/Confusion → " + b("Cerebral Edema → Coma → Death"),
        highlight))
    story.append(SM)

    ucd_data = [
        ["Enzyme Deficiency", "Inheritance", "Severity", "Notes"],
        ["OTC (Ornithine Transcarbamylase)", "X-linked", "Severe", "Most common urea cycle disorder; males severely affected in neonates"],
        ["CPS I deficiency", "Autosomal recessive", "Severe", "No carbamoyl phosphate → complete urea cycle block"],
        ["Argininosuccinate Synthetase\n(Citrullinemia Type I)", "Autosomal recessive", "Severe", "Citrulline accumulates in blood"],
        ["Argininosuccinate Lyase\n(Argininosuccinic aciduria)", "Autosomal recessive", "Moderate-Severe", "Argininosuccinate in blood/urine"],
        ["Arginase I deficiency", "Autosomal recessive", "Mild-Moderate", "Spastic diplegia; seizures; arginine accumulates"],
    ]
    story.append(styled_table(ucd_data, [5.2*cm, 3.2*cm, 2.8*cm, 5*cm]))
    story.append(S)
    story.append(Paragraph(
        b("Key fact:") + " With any urea cycle enzyme defect (except arginase deficiency), "
        b("arginine becomes an essential amino acid") + " because it cannot be synthesized.",
        body))
    story.append(SM)

    tx_data = [
        ["Treatment", "Mechanism", "N Exported"],
        ["Protein restriction + adequate calories", "Reduce nitrogen load; prevent catabolism", "—"],
        ["Phenylbutyrate → phenylacetate\n→ + Glutamine → phenylacetylglutamine", "Excreted in urine; bypasses urea cycle", "2 N per molecule"],
        ["Sodium benzoate → hippurate\n(+ Glycine)", "Excreted in urine", "1 N per molecule"],
        ["Oral neomycin / lactulose", "↓ gut bacteria → ↓ urease activity → ↓ intestinal NH₃", "—"],
        ["Arginine / citrulline supplementation", "Replenish depleted urea cycle intermediates", "—"],
        ["Liver transplant", "Definitive cure — restores full urea cycle enzyme activity", "—"],
    ]
    story.append(styled_table(tx_data, [6*cm, 6.5*cm, 2.5*cm]))
    story.append(PageBreak())

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 10 — HIGH-YIELD SUMMARY TABLES
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("10 ·  High-Yield Summary Tables", TEAL))
    story.append(SM)

    story.append(Paragraph(b("Key Enzymes of Nitrogen Metabolism"), h2))
    enzyme_data = [
        ["Enzyme", "Location", "Coenzyme/\nActivator", "Direction", "Clinical Relevance"],
        ["Aminotransferases\n(ALT, AST)", "All tissues", "PLP (Vit B6)", "Reversible", "Elevated in liver/muscle damage"],
        ["Glutamate\nDehydrogenase (GDH)", "Liver/kidney\nmitochondria", "NAD⁺ / NADP⁺\nGTP ⛔ ADP ✅", "Both", "Releases free NH₃ for urea cycle"],
        ["CPS I", "Mitochondria\n(liver)", "NAG (activator)\n2 ATP consumed", "Irreversible", "Rate-limiting; deficiency → hyperammonemia"],
        ["OTC", "Mitochondria\n(liver)", "—", "Irreversible", "Most common UCD; X-linked"],
        ["Argininosuccinate\nSynthetase (ASS)", "Cytoplasm", "ATP (→ AMP)", "Irreversible", "Citrullinemia Type I if deficient"],
        ["Argininosuccinate\nLyase (ASL)", "Cytoplasm", "—", "Irreversible", "Argininosuccinic aciduria if deficient"],
        ["Arginase I", "Cytoplasm\n(liver only)", "—", "Irreversible", "Liver-exclusive; produces urea"],
        ["Glutamine\nSynthetase", "Most tissues", "ATP", "Irreversible", "Non-toxic NH₃ transport carrier"],
        ["D-Amino Acid\nOxidase (DAO)", "Peroxisomes", "FAD", "Irreversible", "D-serine metabolism; schizophrenia link"],
    ]
    story.append(styled_table(enzyme_data, [3.5*cm, 2.8*cm, 2.8*cm, 2*cm, 5.1*cm]))
    story.append(SM)

    story.append(Paragraph(b("Sources of Ammonia in the Body"), h2))
    nh3_data = [
        ["Source", "Mechanism", "Relative Contribution"],
        ["Amino acid catabolism", "Transdeamination (aminotransferase + GDH)", "Major"],
        ["Glutamine hydrolysis", "Glutaminase in intestine and kidney", "Major"],
        ["Intestinal bacteria", "Urease converts dietary urea → NH₃", "Significant"],
        ["Biogenic amines", "MAO (monoamine oxidase) deaminates amines", "Minor"],
        ["Purine/pyrimidine catabolism", "Deamination during nucleotide breakdown", "Minor"],
    ]
    story.append(styled_table(nh3_data, [4.5*cm, 7*cm, 4.7*cm]))
    story.append(PageBreak())

    # ══════════════════════════════════════════════════════════════════════════
    # SECTION 11 — EXAM ONE-LINERS
    # ══════════════════════════════════════════════════════════════════════════
    story.append(section_header("11 ·  Exam One-Liners & Memory Tricks", ACCENT_GOLD))
    story.append(SM)

    story.append(Paragraph(b("★ Must-Know One-Liners"), h2))
    oneliner_data = [
        ["#", "One-Liner", "Why it matters"],
        ["1", "Amino acids CANNOT be stored — excess is degraded.", "Foundation of the whole chapter"],
        ["2", "Lysine and Threonine do NOT transaminate.", "Exam trap; all others do"],
        ["3", "ALL aminotransferases require PLP (Vitamin B6).", "Any B6 deficiency impairs nitrogen removal"],
        ["4", "ALT is more liver-specific than AST.", "MI raises AST but not ALT significantly"],
        ["5", "Glutamate is the central nitrogen collector.", "All roads lead to glutamate first"],
        ["6", "GDH: GTP inhibits, ADP activates.", "Energy status controls amino acid catabolism"],
        ["7", "CPS I is the rate-limiting step of the urea cycle.", "Activated by NAG (not by substrate alone)"],
        ["8", "NAG = essential allosteric activator of CPS I.", "No NAG = no urea synthesis"],
        ["9", "Arginine activates NAGS → more NAG → more CPS I.", "Positive feedback after protein-rich meal"],
        ["10", "OTC deficiency = most common urea cycle disorder; X-linked.", "Males affected severely; presents in newborns"],
        ["11", "All other urea cycle disorders = autosomal recessive.", "OTC is the only X-linked one"],
        ["12", "4 ATP equivalents consumed per urea molecule.", "Highly exergonic → irreversible"],
        ["13", "2 nitrogens in urea: 1 from NH₃ (GDH), 1 from aspartate (AST).", "Both ultimately from glutamate"],
        ["14", "Arginase I is exclusive to the liver.", "Only liver can complete the full urea cycle"],
        ["15", "Cystinuria = COAL defect → kidney stones.", "Cystine, Ornithine, Arginine, Lysine"],
        ["16", "Hartnup = tryptophan transport defect → pellagra-like.", "Dermatitis, diarrhea, dementia (3 D's)"],
        ["17", "Enteropeptidase activates trypsinogen → trypsin activates all others.", "Master switch of pancreatic digestion"],
        ["18", "Phenylbutyrate exports 2 N; benzoate exports 1 N.", "Nitrogen scavenger drugs for hyperammonemia"],
        ["19", "In urea cycle defects, arginine becomes essential.", "Cannot be synthesized; must be supplemented"],
        ["20", "Branched-chain AAs (Val, Leu, Ile) bypass liver → muscle.", "Oxidized in muscle, not liver"],
    ]
    story.append(styled_table(oneliner_data, [0.8*cm, 9.5*cm, 5.9*cm]))
    story.append(SM)

    story.append(Paragraph(b("Memory Tricks"), h2))
    tricks = [
        ("Urea Cycle Steps", '"Can Citrulline Always Act Usefully?" = Carbamoyl-P → Citrulline → Argininosuccinate → Arginine → Urea'),
        ("COAL transport defect", '"COAL" = Cystine, Ornithine, Arginine, Lysine — all deficient in Cystinuria'),
        ("GDH regulation", '"GTP = Got Too much energy → stop degrading. ADP = A Deficit of energy → go degrade."'),
        ("PLP coenzyme", "B6 → PLP → ALL transaminations. If you see any aminotransferase, think Vitamin B6."),
        ("Urea nitrogens", "NH₃ from GDH (mito) = nitrogen #1. Aspartate from AST (cyto) = nitrogen #2."),
        ("OTC deficiency", "OTC = Only The Child (male newborn); X-linked; urea cycle shuts down → hyperammonemia."),
    ]
    for title, trick in tricks:
        story.append(KeyBox([f"{title}: {trick}"], bg=LIGHT_PURP, border=ACCENT_PURP))
        story.append(Spacer(1, 4))
    story.append(SM)

    # ── FINAL FLOW SUMMARY ─────────────────────────────────────────────────────
    story.append(section_header("★  Master Summary Flow", DEEP_NAVY))
    story.append(SM)
    flow_data = [
        ["Stage", "Process", "Key Enzyme/Agent", "Product"],
        ["Dietary protein", "Digestion (stomach, pancreas, brush border)", "Pepsin → Trypsin → Aminopeptidase", "Free amino acids"],
        ["Absorption", "Na⁺ / H⁺ cotransport into enterocytes", "PepT1 for di/tripeptides", "AAs → portal blood"],
        ["Nitrogen removal (Step 1)", "Transamination to α-ketoglutarate", "Aminotransferases (PLP)", "Glutamate + α-keto acid"],
        ["Nitrogen removal (Step 2)", "Oxidative deamination of glutamate", "GDH (NAD⁺; ADP activates)", "Free NH₃ + α-KG"],
        ["NH₃ transport (general)", "Packaging into glutamine", "Glutamine synthetase (ATP)", "Glutamine → liver"],
        ["NH₃ transport (muscle)", "Packaging into alanine", "ALT (Glucose-Alanine Cycle)", "Alanine → liver"],
        ["Urea synthesis (Mito 1)", "Carbamoyl phosphate formation", "CPS I (NAG activator)", "Carbamoyl-P"],
        ["Urea synthesis (Mito 2)", "Citrulline formation", "OTC", "Citrulline → cytoplasm"],
        ["Urea synthesis (Cyto 3)", "Argininosuccinate synthesis", "ASS (ATP)", "Argininosuccinate"],
        ["Urea synthesis (Cyto 4)", "Argininosuccinate cleavage", "ASL", "Arginine + Fumarate"],
        ["Urea synthesis (Cyto 5)", "Urea formation", "Arginase I (liver only)", "Urea + Ornithine"],
        ["Excretion", "Blood → kidneys → urine", "Renal filtration", "Urea excreted"],
    ]
    story.append(styled_table(flow_data, [4*cm, 5*cm, 4.5*cm, 2.7*cm]))
    story.append(SM)
    story.append(Paragraph(
        "All content based on: " + b("Lippincott's Illustrated Reviews: Biochemistry, Chapter 19") +
        " — Amino Acids: Disposal of Nitrogen.",
        caption))

    doc.build(story)
    print(f"PDF created: {OUTPUT}")

build_pdf()

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